WO2025250184A1 - Compositions de cuivre-64 et procédés de purification pour la préparation de nouvelles compositions de cuivre-64 - Google Patents

Compositions de cuivre-64 et procédés de purification pour la préparation de nouvelles compositions de cuivre-64

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Publication number
WO2025250184A1
WO2025250184A1 PCT/US2024/060406 US2024060406W WO2025250184A1 WO 2025250184 A1 WO2025250184 A1 WO 2025250184A1 US 2024060406 W US2024060406 W US 2024060406W WO 2025250184 A1 WO2025250184 A1 WO 2025250184A1
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Prior art keywords
composition
mci
target
hcl
less
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English (en)
Inventor
Brian REGNA
Lars LINDSKOG
Lauren RADFORD
Jeffrey Randick
Shaun LOVELESS
Allan CASCIOLA
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Curium US LLC
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Curium US LLC
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Priority claimed from US18/745,888 external-priority patent/US20250197238A1/en
Application filed by Curium US LLC filed Critical Curium US LLC
Publication of WO2025250184A1 publication Critical patent/WO2025250184A1/fr
Pending legal-status Critical Current
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • G—PHYSICS
    • G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
    • G21G—CONVERSION OF CHEMICAL ELEMENTS; RADIOACTIVE SOURCES
    • G21G1/00—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes
    • G21G1/04—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators
    • G21G1/10—Arrangements for converting chemical elements by electromagnetic radiation, corpuscular radiation or particle bombardment, e.g. producing radioactive isotopes outside nuclear reactors or particle accelerators by bombardment with electrically charged particles

Definitions

  • FIELD 63/521,580, filed June 16, 2023, the entire contents of each of which are incorporated by reference herein.
  • FIELD [0002] The present disclosure relates to novel compositions comprising high levels of copper-64 (e.g., high radionuclidic purity, high activity, and/or high specific activity), and processes for preparing said compositions.
  • BACKGROUND [0003] Diagnostic nuclear medicine primarily uses two imaging techniques – single photon emission tomography (SPECT) and positron emission tomography (PET), often in conjunction with computerized tomography (CT) or magnetic resonance imaging (MRI). Of the two imaging techniques, PET provides higher resolution images and quantitative information.
  • CT computerized tomography
  • MRI magnetic resonance imaging
  • PET isotopes include oxygen-15 ( 15 O), nitrogen-13 ( 13 N), carbon-11 ( 11 C), fluorine-18 ( 18 F), and gallium-68 ( 68 Ga). Each of these isotopes, however, has a relatively short half-life, which necessitates producing them in close proximity to the PET imaging device and incorporating them into imaging agents before excessive radioactive decay or drug product decomposition occurs.
  • a generator system for 68 Ga is available but it can be difficult to obtain and severely limits the number 1 100563663.1 Atty.
  • positron energy of 278.2 keV provides high resolution images, and its moderate half-life (12.7 h) is suitably long to allow for production, purification, incorporation into a carrier molecule (e.g., peptide, small-molecule, antibody, etc.) and distribution to medical facilities as an end-use product.
  • a carrier molecule e.g., peptide, small-molecule, antibody, etc.
  • 64 Cu i.e., Ci or GBq amounts
  • 64 Cu copper chloride for use as a radioactive precursor.
  • Preparations of 64 Cu copper chloride have been produced from isotopically enriched nickel-64 ( 64 Ni) targets, and the 64 Cu has been purified using ion exchange chromatography.
  • the highest reported amount of 64 Cu produced was 1.5 Ci, reported at end of bombardment (EOB). While this amount is sufficient for preparing patient doses, when factoring in decay and yield loss during manufacturing (i.e., formulation, sterilization, dispense, quality control, packaging and shipment) – 1.5 Ci of 64 Cu at EOB may yield 50 patient doses in a best-case scenario (assuming an average patient dose of 4 mCi, 32 h for manufacturing and shipment and 15% yield loss). The number of theoretical patient doses may be significantly improved by increasing the available quantity of 64 Cu copper chloride precursor.
  • the 64 Cu must be of high chemical and radionuclidic purity.
  • Specific activity i.e., activity of 64 Cu per mass of total Cu
  • 64 Cu copper chloride is an indicator of its chemical purity and is often expressed in units of mCi/ ⁇ g or Ci/mmol.
  • the highest reported specific activity of purified 64 Cu copper chloride was 348 mCi/ ⁇ g Cu. This is sufficient for radiolabeling, but improvements in specific activity may improve the purity and reactivity of a radioactive precursor, thereby decreasing the required amount of carrier molecule necessary in production of a radiolabeled pharmaceutical. This has implications for patient safety and may enhance the diagnostic capability of a radiopharmaceutical. Improvements in specific 2 100563663.1 Atty.
  • WO1 activity of 64 Cu may be made by increasing the produced quantity of radioactive precursor, limiting the potential for introduction of trace metallic contaminants and creating a robust purification process.
  • 64 Cu were widely available, it would enhance the capabilities of existing PET centers and would also allow PET studies to be performed at medical centers that do not have an on-site 68 Ge/ 68 Ga generator and/or do not rely on a regional cyclotron. Described herein are methods of making purified 64 Cu having improved chemical and radionuclidic purities and a specific activity that is favorable for supplying commercial clinical needs of PET and medical centers.
  • compositions comprising high levels of 64 Cu with high purity and high specific activity and processes for preparing said compositions.
  • One aspect of the present disclosure provides a composition comprising from about 2 Ci to about 110 Ci of 64 Cu, about 5 Ci to about 110 Ci of 64 Cu, about 9 Ci to about 110 Ci of 64 Cu, about 12 Ci to about 110 Ci of 64 Cu, about 15 Ci to about 110 Ci of 64 Cu, about 18 Ci to about 110 Ci of 64 Cu, or about 20 Ci to about 110 Ci of 64 Cu at end of bombardment (EOB).
  • the compositions of the present invention may further be characterized as pharmaceutical grade, suitable for human administration, and/or suitable for administration to a human subject in need thereof.
  • compositions of the present invention may be suitable for administration to a human subject in need thereof once divided into a smaller aliquot.
  • the present invention includes a method comprising applying a proton beam from about 250 ⁇ A to about 300 ⁇ A, from about 300 ⁇ A to about 350 ⁇ A, from about 350 ⁇ A to about 400 ⁇ A, from about 450 ⁇ A to about 500 ⁇ A, from about 550 ⁇ A to about 600 ⁇ A, from about 600 ⁇ A to about 650 ⁇ A, from about 650 ⁇ A to about 700 ⁇ A, from about 700 ⁇ A to about 750 ⁇ A, from about 750 ⁇ A to about 800 ⁇ A, from about 800 ⁇ A to about 850 ⁇ A, from about 850 ⁇ A to about 900 ⁇ A, from about 900 ⁇ A to about 950 ⁇ A, from about 950 ⁇ A to about 1000 ⁇ A, from about 1000 ⁇ A to about 1050 ⁇ A, from about 1050 ⁇ A to about 1100
  • the current of the proton beam may be split between two targets or a plurality of targets.
  • the current of the proton beam to each target may range from about 190 ⁇ A to about 230 ⁇ A, from about 200 ⁇ A to about 225 ⁇ A, from about 250 ⁇ A to about 300 ⁇ A, from about 300 ⁇ A to about 350 ⁇ A, or from about 350 ⁇ A to about 410 ⁇ A, from about 405 ⁇ A to about 410 ⁇ A, about 410 ⁇ A to about 420 ⁇ A, about 420 ⁇ A to about 440 ⁇ A, 440 ⁇ A to about 460 ⁇ A, or about 460 ⁇ A to about 480 ⁇ A.
  • the current of the proton beam may be about 300 ⁇ A, about 400 ⁇ A, about 408 ⁇ A, about 410 ⁇ A or about 500 ⁇ A.
  • Another aspect of the present invention includes a method comprising bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target comprising from 20 Ci to about 110 Ci of 64 Cu at end of bombardment (EOB), wherein the proton beam is a high amperage proton beam ( ⁇ 300 ⁇ A) or a very high amperage proton beam ( ⁇ 400 ⁇ A), and wherein the proton beam of the cyclotron has an energy of less than about 30 MeV on the target .
  • the bombarded target may comprise from about 15.0-95.0 Ci of 64 Cu, including from about 20.0-85.0 Ci of 64 Cu, from about 25.0- 80.0 Ci of 64 Cu, from about 30.0-75.0 C of 64 Cu, and from about 40.0-70.0 Ci of 64 Cu.
  • the bombarded target may comprise from about 20.0-95.0 Ci, from about 20.0-90.0 Ci, from about 20.0-85.0 Ci, from about 20.0-80.0 Ci, from about 20.0-75.0 Ci, and from about 20.0-70.0 Ci of 64 Cu.
  • the bombarded target may comprise from about 15.0-25.0 Ci, from about 25.0-35.0 Ci, from about 35.0-45.0 Ci, from about 45.0-55.0 Ci, from about 55.0-65.0 Ci, from about 65.0-75.0 Ci, from about 75.0-85.0 Ci, and from about 85.0-95.0 Ci of 64 Cu.
  • the bombarded target may comprise ⁇ 17.5 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu, ⁇ 22.5 Ci of 64 Cu, ⁇ 25 Ci of 64 Cu, ⁇ 30 Ci of 64 Cu, ⁇ 35 Ci of 64 Cu, ⁇ 40 Ci of 64 Cu, ⁇ 45 Ci of 64 Cu, ⁇ 50 Ci of 64 Cu, ⁇ 55 Ci of 64 Cu, ⁇ 60 Ci of 64 Cu, ⁇ 65 Ci of 64 Cu, ⁇ 70 Ci of 64 Cu, ⁇ 75 Ci of 64 Cu, ⁇ 80 Ci of 64 Cu, ⁇ 85 Ci of 64 Cu ⁇ ⁇ 90 Ci of 64 Cu, ⁇ 95 Ci of 64 Cu, and/or ⁇ 100 Ci of 64 Cu.
  • the composition may be obtained from a single target during one cyclotron run.
  • the composition may have a specific activity at least about 25 mCi 64 Cu/ ⁇ g Cu, at least about 30 mCi 64 Cu/ ⁇ g Cu, at least about 35 mCi 64 Cu/ ⁇ g Cu, at least about 40 mCi 64 Cu/ ⁇ g Cu, at least about 45 mCi 64 Cu/ ⁇ g Cu, at least about 50 mCi 64 Cu/ ⁇ g Cu, at least about 55 mCi 64 Cu/ ⁇ g Cu, at least about 60 mCi 64 Cu/ ⁇ g Cu, at least about 65 mCi 64 Cu/ ⁇ g Cu, at least about 70 mCi 64 Cu/ ⁇ g Cu, at least about 75 mCi 64 Cu/ ⁇ g Cu, at least about 80 mCi 64 Cu/ ⁇ g Cu, at least about 85 mCi 64 Cu/ ⁇ g Cu, at least about 90 mCi 64 Cu/ ⁇ g Cu
  • the composition may have a specific activity up to about 3750 mCi 64 Cu/ ⁇ g Cu, about 3775 mCi 64 Cu/ ⁇ g Cu about 3800 mCi 64 Cu/ ⁇ g Cu, about 3825 mCi 64 Cu/ ⁇ g Cu, or about 3850 mCi 64 Cu/ ⁇ g Cu.
  • the composition may have a specific activity at least about 30 mCi 64 Cu/ ⁇ g Cu up to about 3750 mCi 64 Cu/ ⁇ g Cu, at least about 30 mCi 64 Cu/ ⁇ g Cu up to about 3775 mCi 64 Cu/ ⁇ g, at least about 30 mCi 64 Cu/ ⁇ g Cu up to about 3800 mCi 64 Cu/ ⁇ g Cu, at least about 30 mCi 64 Cu/ ⁇ g Cu up to about 3825 mCi 64 Cu/ ⁇ g Cu, or at least about 30 mCi 64 Cu/ ⁇ g Cu up to about 3850 mCi 64 Cu/ ⁇ g Cu.
  • the composition may have a specific activity at least about 40 mCi 64 Cu/ ⁇ g Cu up to about 3750 mCi 64 Cu/ ⁇ g Cu, at least about 40 mCi 64 Cu/ ⁇ g Cu up to about 3775 mCi 64 Cu/ ⁇ g, at least about 40 mCi 64 Cu/ ⁇ g Cu up to about 3800 mCi 64 Cu/ ⁇ g Cu, at least about 40 mCi 64 Cu/ ⁇ g Cu up to about 3825 mCi 64 Cu/ ⁇ g Cu, or at least about 40 mCi 64 Cu/ ⁇ g Cu up to about 3850 mCi 64 Cu/ ⁇ g Cu.
  • the composition may have a specific activity of at least about 50 mCi 64 Cu/ ⁇ g Cu up to about 3750 mCi 64 Cu/ ⁇ g Cu, at least about 50 mCi 64 Cu/ ⁇ g Cu up to about 3775 mCi 64 Cu/ ⁇ g, at least about 50 mCi 64 Cu/ ⁇ g Cu up to about 3800 mCi 64 Cu/ ⁇ g Cu, at least about 50 mCi 64 Cu/ ⁇ g Cu up to about 3825 mCi 64 Cu/ ⁇ g Cu, or at least about 50 mCi 64 Cu/ ⁇ g Cu up to about 3850 mCi 64 Cu/ ⁇ g Cu.
  • the composition may have a specific activity at least about 50 mCi 64 Cu/ ⁇ g Cu up to about 3750 mCi 64 Cu/ ⁇ g Cu, about 3775 mCi 64 Cu/ ⁇ g Cu about 3800 mCi 64 Cu/ ⁇ g Cu, about 3825 mCi 64 Cu/ ⁇ g Cu, or about 3850 mCi 64 Cu/ ⁇ g Cu.
  • the composition may have a specific activity at least about 75 mCi 64 Cu/ ⁇ g Cu up to about 3750 mCi 64 Cu/ ⁇ g Cu, 5 100563663.1 Atty. Docket No.
  • C-US-009 WO1 about 3775 mCi 64 Cu/ ⁇ g Cu about 3800 mCi 64 Cu/ ⁇ g Cu, about 3825 mCi 64 Cu/ ⁇ g Cu, or about 3850 mCi 64 Cu/ ⁇ g Cu.
  • the composition may have a specific activity at least about 100 mCi 64 Cu/ ⁇ g Cu up to about 3750 mCi 64 Cu/ ⁇ g Cu, about 3775 mCi 64 Cu/ ⁇ g Cu about 3800 mCi 64 Cu/ ⁇ g Cu, about 3825 mCi 64 Cu/ ⁇ g Cu, or about 3850 mCi 64 Cu/ ⁇ g Cu or higher.
  • the composition comprises a solution of hydrochloric acid, such that the 64 Cu exists as 64 CuCl2.
  • a further aspect of the present disclosure encompasses a process for preparing the 64 Cu from 64 Ni.
  • the process comprises (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of HCl having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni and 64 Cu; and (c) purifying the 64 Cu from the strip solution by ion exchange chromatography, wherein the ion exchange chromatography comprises (i) passing the strip solution through a column comprising an ion exchange resin such that 64 Cu binds to the ion exchange resin and 64 Ni passes through the column as a flow-through; (ii) rinsing the column with a volume of HCl having a molarity of about 3 M to about 6 M; and
  • Another aspect of the present disclosure encompasses an additional process for purifying the 64 Cu from other metals in the strip solution by using a packed bed ion exchange chromatography column.
  • the process comprises (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of HCl having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and other metals; and (c) purifying the 64 Cu from the strip solution by chromatography, wherein the chromatography comprises (i) passing the strip solution through an ion exchange resin such that the 64 Cu and 61 Co bind to the ion exchange resin in the column, and 64 Ni passes through as a first flow-through fraction; (ii) rinsing the column with a volume of HCl having a molarity of about 6 M to about 12.1 M to remove residual 64 Ni as a second
  • FIG. 10 Another aspect of the present disclosure encompasses an additional process for preparing 64 Cu from 64 Ni, wherein the 64 Cu is purified by a combination of extraction chromatography and ion exchange chromatography.
  • the process comprises (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of HCl having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and one or more other metals; and (c) purifying the 64 Cu from the strip solution by chromatography, wherein the chromatography comprises (i) passing the strip solution through a first column comprising an extraction resin connected in series to a second column comprising an ion exchange resin, such that the one or more other metals binds to the extraction resin in the first column, 64 Cu and 61 Co bind to the ion exchange resin in the second column, and 64 Ni passes through both columns as a first flow-through fraction.
  • the process further comprises (ii) rinsing the first and second columns with a volume of HCl having a molarity of about 6 M to about 12.1 M to remover residual 64 Ni as a second flow-through fraction; (iii) rinsing the second column with a volume of HCl having a molarity of about 3 M to about 6 M to elute 61 Co as a first waste fraction; (iv) rinsing the second column with a volume of NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M or with a volume of HCl having a molarity of about 3 M to about 6 M to elute residual 61 Co as a second waste fraction; and (v) adding a volume of HCl having a molarity of about 0.01 M to about 3 M to the second column to elute the 64 Cu as a product fraction comprising 64 Cu.
  • FIG.1 presents a schematic of the purification process comprising ion exchange chromatography.
  • FIGs.2A, 2B, 2C, and 2D present various embodiments of the purification process comprising a combination of extraction chromatography and ion exchange chromatography.
  • FIG.3 is a plot of proton energy as a function of proton beam radius.
  • FIGs.4A and 4B present various embodiments of the process to improve the radiochemical purity of a radiopharmaceutical composition.
  • FIG.5A shows plated natural nickel target used in a bombardment (Run 1).
  • FIG.5B shows bombarded and stripped natural nickel-plated target (Run 1).
  • FIG.5C shows Ni-64 plated targets (Runs 2-4).
  • FIG.5D shows bombarded and stripped Ni-64 plated target 30Jul24- PB3-2.
  • FIG.5E shows bombarded and stripped Ni-64 plated target 30Jul24- PB2-1.
  • FIG.5F shows bombarded and stripped Ni-64 plated target 30Jul24- PB4-3.
  • FIG.6A shows stopping power for a hydrogen ion in Nickel-58. Blue dots represent the calculated values from SRIM and the red line represents the fit associated with the displayed equation.
  • FIG.6B shows stopping power for a hydrogen ion in Nickel-64. Blue dots represent the calculated values from SRIM and the red line represents the fit associated with the displayed equation.
  • FIG.6C shows an example of proton beam hitting a nickel target electroplated on a gold plate.
  • FIG.6D shows proton energy as a function of the actual thickness of a plate.
  • FIG.6E shows the fits used to solve the 64 Ni(p,n) 64 Cu cross section. 8 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1
  • FIG.7A shows a graphical comparison of the experimentally and theoretically determined activities of radioactive isotopes produced during the bombardment of a natural nickel target with a 13 MeV proton beam at 150 ⁇ A for 0.5 hr (Run 1).
  • FIG.7B shows a graphical comparison of the experimentally and theoretically determined activities of radioactive isotopes produced during the bombardment of an enriched Ni-64 target with a 13 MeV proton beam at 150 ⁇ A for 1 hr (Run 2).
  • FIG.7C shows a graphical comparison of the experimentally and theoretically determined activities of radioactive isotopes produced during the bombardment of an enriched Ni-64 target with a 13 MeV proton beam at 375 ⁇ A for 2 hr 11 min (Run 3).
  • FIG.7D shows a graphical comparison of estimated activity and theoretical calculations of the isotopes produced by a new cyclotron during Run 3.
  • FIG.7E shows a graphical comparison of the experimentally and theoretically determined activities of radioactive isotopes produced during the bombardment of an enriched Ni-64 target with a 13 MeV proton beam at 375 ⁇ A for 4 hr 23 min (Run 4).
  • FIG.7F shows a graphical comparison of the experimentally determined activities of radioactive isotopes produced during the bombardment of natural nickel (run 1) and enriched Ni-64 (run 2, 3, and 4) targets.
  • FIG.7G shows 6 theoretical calculations estimating the Asat of Cu-64 production as a function of the plated mass and beam energy.
  • FIG.7H shows theoretical calculations estimating saturation yield of Co-61 production as a function of the plated mass and beam energy.
  • FIG.7I shows saturation yields as a function of target weight determined using SRIM calculations to determine proton beam exit energy. Determined using the calculation of the exit energy for 1000 protons.
  • FIG.7J shows saturation yields for Cu-64 as a function of the beam energy. Calculated for a mass loading of 0.50, 0.65, and 0.80 g of enriched Ni-64 9 100563663.1 Atty. Docket No.
  • FIG.7K shows saturation yields for various isotopic impurities as a function of the beam energy. Calculated for a mass loading of 0.65 g of enriched Ni-64 (weight percents: Ni-58: 2.40%, Ni-60: 1.41%, Ni-61: 0.13%, Ni-62: 0.66%, Ni-64: 95.4%). Isotope predictions were kept within the beam energies of the polynomial fit to their experimental data.
  • compositions comprising high levels of high specific activity 64 Cu and processes for preparing said compositions.
  • the 64 Cu compositions described herein are suitable for administration to a human patient in need thereof.
  • the 64 Cu compositions described herein are suitable for administration via injection.
  • the processes disclosed herein are able to produce high levels of 64 Cu from a single target during one continuous cyclotron bombardment (i.e., cyclotron run).
  • the 64 Cu produced by these processes has a high specific activity, as well as high chemical and radionuclidic purities. Radionuclidic purity is a measurement of the percent of total radioactivity that is due to the desired radioisotope in a given composition.
  • the 64 Cu compositions produced by the processes disclosed herein also have low levels of metal impurities such as cobalt, iron, nickel and lead.
  • the 64 Cu compositions produced by the processes disclosed herein also have low levels of 67 Cu or an absence of 67 Cu (i.e., zero ppm 67 Cu).
  • the 64 Cu compositions produced by the processes disclosed herein also have low levels of 68 Zn or an absence of 68 Zn (i.e., zero ppm 68 Zn).
  • the 64 Cu compositions produced by the processes disclosed herein also have low levels of or an absence of any element or isotope with a mass number of 67 or greater.
  • the 64 Cu compositions produced by the processes disclosed herein also have low levels of or an absence of any element or isotope with a mass number of 68 or 10 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 greater.
  • the 64 Cu compositions produced by the processes disclosed herein also have an absence of zinc-based target source materials (i.e., 0 ppm).
  • the 64 Cu compositions disclosed herein may comprise high levels of high specific activity 64 Cu.
  • the 64 Cu compositions described herein include isolated 64 Cu compositions, wherien the 64 Cu has been removed or stripped from the target.
  • the 64 Cu compositions comprise up to about 110 Ci of 64 Cu and have specific activities up to about 4800 mCi 64 Cu/ ⁇ g Cu.
  • the 64 Cu compositions comprise up to about 110 Ci of 64 Cu and have specific activities from 30 mCi 64 Cu/ ⁇ g Cu up to about 4800 mCi 64 Cu/ ⁇ g Cu.
  • the 64 Cu compositions comprise up to about 110 Ci of 64 Cu and have specific activities from 40 mCi 64 Cu/ ⁇ g Cu up to about 4800 mCi 64 Cu/ ⁇ g Cu.
  • the 64 Cu compositions comprise up to about 110 Ci of 64 Cu and have specific activities from 50 mCi 64 Cu/ ⁇ g Cu up to about 4800 mCi 64 Cu/ ⁇ g Cu.
  • the 64 Cu compositions may be prepared by the processes described below in sections (II) to (IV). [0045]
  • the 64 Cu activity (Ci or Bq) may be measured by gamma spectroscopy (e.g., high purity germanium (HPGe) detector), a dose calibrator, or similar means.
  • HPGe high purity germanium
  • compositions described herein may be suitable for administration to a human patient in need thereof.
  • the compositions described herein may be suitable for administration via a single dose vial.
  • the compositions described herein comprise about 35 MBq to about 40 MBq of 64 Cu per 1 mL of the composition in a single dose vial.
  • compositions described herein comprise about 35 MBq to about 40 MBq of 64 Cu DOTATATE per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 36 MBq to about 38 MBq of 64 Cu per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 36 MBq to about 38 MBq of 64 Cu DOTATATE per 1 mL of the composition in a single dose 11 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 vial.
  • compositions described herein comprise about 36.5 MBq to about 37.5 MBq of 64 Cu per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 36.5 MBq to about 37.5 MBq of 64 Cu per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 36.5 MBq to about 37.5 MBq of 64 Cu DOTATATE per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 37.0 MBq of 64 Cu DOTATATE per 1 mL of the composition in a single dose vial.
  • compositions described herein comprise about 145 to about 150 MBq of 64 Cu DOTATATE per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 145 to about 150 MBq of 64 Cu per 1 mL of the composition in a single dose vial. In another aspect, the compositions described herein comprise about 145 to about 150 MBq of 64 Cu in a single dose vial, wherein the composition further comprises DOTA and/or DOTAGA.
  • composition in the single dose vial suitable for administration to a human patient in need thereof may be isolated or aliquoted from a composition comprising from 15 Ci to 110 Ci of 64 Cu and having a specific activity from 50 mCi to 3850 mCi 64 Cu/ ⁇ g Cu.
  • the compositions in the single dose vial(s) may also have low levels of 67 Cu or a complete absence of 67 Cu (i.e., zero ppm 67 Cu or zero ppb 67 Cu).
  • the compositions in the single dose vial produced by the processes disclosed herein may also have low levels of 68 Zn or a complete absence of 68 Zn (i.e., zero ppm 68 Zn or zero ppb 68 Zn).
  • compositions in the single dose vial may also have low levels of or an absence of any element or isotope with a mass number of 67 or greater.
  • the composition in the single dose vials produced by the processes disclosed herein may also have low levels of or an absence of any element or isotope with a mass number of 68 or greater.
  • the composition in the single dose vials produced by the processes disclosed herein have an absence of zinc-based target source materials.
  • the compositions disclosed herein may comprise from about 2 Ci to about 15 Ci of 64 Cu at the end of bombardment (EOB).
  • the level of 64 Cu may be determined at EOB or a later time point. Persons skilled in the art understand that the level of 64 Cu activity decreases over time.
  • the 12 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 compositions may comprise from about 2 Ci to about 3 Ci, from about 3 Ci to about 4 Ci, from about 4 Ci to about 5 Ci, from about 5 Ci to about 6 Ci, from about 6 Ci to about 7 Ci, from about 7 Ci to about 8 Ci, from about 8 Ci to about 9 Ci, from about 9 Ci to about 10 Ci, from about 10 Ci to about 11 Ci, from about 11 Ci to about 12 Ci, from about 12 Ci to about 13 Ci, from about 13 Ci to about 14 Ci, or from about 14 Ci to about 15 Ci of 64 Cu.
  • the composition may comprise from about 4.0-4.5 Ci, from about 4.5-5.0 Ci, from about 5.0-5.5 Ci, from about 5.5-6.0 Ci, from about 6.0-6.5 Ci, from about 6.5-7.0 Ci, from about 7.0-7.5 Ci, from about 7.5-8.0 Ci, from about 8.0-8.5 Ci, from about 8.5-9.0 Ci, from about 9.0-12.0 Ci, from about 12.0- 15.0 Ci, from about 4.0-5.5 Ci, from about 5.5-7.0 Ci, from about 6.0-7.5 Ci, from about 7.0-8.5 Ci, r from about 7.5-9.0 Ci, or from about 9.0-15.0 Ci of 64 Cu.
  • the composition may comprise from about 4.0-15.5 Ci, from about 4.5- 15.0 Ci, from about 5.0-15.0 Ci, from about 5.5-15.0 Ci, from about 6.0-15.0 Ci, from about 6.5-15.0 Ci, from about 7.0-15.0 Ci, from about 7.5-15.0 Ci, from about 8.0-15.0 Ci, from about 8.5-15.0 Ci, from about 9.0-15.0 Ci, from about 9.5-15.0 Ci, from about 10.0-15.0 Ci, from about 10.5-15.0 Ci, from about 11.0-15.0 Ci, from about 11.5-15.0 Ci, from about 12.0-15.0 Ci, from about 12.5-15.0 Ci, or from about 13.0-15.0 Ci of 64 Cu.
  • the composition may comprise from about 15.0-25.0 Ci, including from about 16.0-24.0 Ci, from about 17.0-23.0 Ci, from about 18.0-22.0 Ci, from about 19.0-21.0 Ci, or from about 17.0-20.0 Ci of 64 Cu.
  • the composition may comprise from about 15.0-95.0 Ci, including from about 20.0-85.0 Ci, from about 25.0-80.0 Ci, from about 30.0-75.0 Ci, or from about 40.0-70.0 Ci of 64 Cu.
  • the composition may comprise from about 15.0-100.0 Ci, including from about 20.0-100.0 Ci, from about 25.0-100.0 Ci, from about 30.0-100.0 Ci, or from about 50.0-100.0 Ci of 64 Cu.
  • the composition may comprise from about 20.0-95.0 Ci, from about 20.0-90.0 Ci, from about 20.0-85.0 Ci, from about 20.0-80.0 Ci, from about 20.0-75.0 Ci, and from about 20.0-70.0 Ci of 64 Cu.
  • the composition may comprise from about 15.0-25.0 Ci, from about 25.0-35.0 Ci, from about 35.0-45.0 Ci, from about 45.0- 55.0 Ci, from about 55.0-65.0 Ci, from about 65.0-75.0 Ci, from about 75.0-85.0 Ci, and from about 85.0-95.0 Ci of 64 Cu. 13 100563663.1 Atty. Docket No.
  • the composition may comprise from about 15.0-110.0 Ci, including from about 20.0-110.0 Ci, from about 25.0-110.0 Ci, from about 30.0-110.0 Ci, or from about 50.0-110.0 Ci of 64 Cu.
  • the composition may comprise from about 20.0-95.0 Ci, from about 20.0-90.0 Ci, from about 20.0-85.0 Ci, from about 20.0- 80.0 Ci, from about 20.0-75.0 Ci, and from about 20.0-70.0 Ci of 64 Cu.
  • the composition may comprise from about 15.0-35.0 Ci, from about 25.0- 35.0 Ci, from about 35.0-45.0 Ci, from about 45.0-55.0 Ci, from about 55.0-65.0 Ci, from about 65.0-75.0 Ci, from about 75.0-85.0 Ci, and from about 85.0-95.0 Ci of 64 Cu.
  • the composition may comprise ⁇ 15 Ci of 64 Cu, ⁇ 17.5 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu, ⁇ 22.5 Ci of 64 Cu, ⁇ 25 Ci of 64 Cu, ⁇ 30 Ci of 64 Cu, ⁇ 35 Ci of 64 Cu, ⁇ 40 Ci of 64 Cu, ⁇ 45 Ci of 64 Cu, ⁇ 50 Ci of 64 Cu, ⁇ 55 Ci of 64 Cu, ⁇ 60 Ci of 64 Cu, ⁇ 65 Ci of 64 Cu, ⁇ 70 Ci of 64 Cu, ⁇ 75 Ci of 64 Cu, ⁇ 80 Ci of 64 Cu, ⁇ 85 Ci of 64 Cu ⁇ ⁇ 90 Ci of 64 Cu, ⁇ 95 Ci of 64 Cu, and/or ⁇ 100 Ci of 64 Cu at EOB.
  • the composition may comprise at least about 15 Ci of 64 Cu, at least about 17.5 Ci of 64 Cu, at least about 20 Ci of 64 Cu, at least about 25 Ci of 64 Cu, at least about 30 Ci of 64 Cu, at least about 35 Ci of 64 Cu, at least about 40 Ci of 64 Cu, at least about 45 Ci of 64 Cu, at least about 50 Ci of 64 Cu, at least about 55 Ci of 64 Cu, at least about 60 Ci of 64 Cu, at least about 65 Ci of 64 Cu, at least about 70 Ci of 64 Cu, at least about 75 Ci of 64 Cu, at least about 80 Ci of 64 Cu, at least about 85 Ci of 64 Cu, at least about 90 Ci of 64 Cu, at least about 95 Ci of 64 Cu, or at least about 100 Ci of 64 Cu.
  • the composition may comprise ⁇ 20 Ci of 64 Cu and ⁇ 100 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu and ⁇ 90 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu and ⁇ 80 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu and ⁇ 70 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu and ⁇ 60 of Ci 64 Cu, ⁇ 20 Ci of 64 Cu and ⁇ 50 Ci of 64 Cu, ⁇ 50 Ci of 64 Cu and ⁇ 100 Ci of 64 Cu.
  • the composition may also comprise ⁇ 90.0% purity of 64 Cu, ⁇ 90.5% purity of 64 Cu, ⁇ 91.0% purity of 64 Cu, ⁇ 91.5% purity of 64 Cu, ⁇ 92.0% purity of 64 Cu, ⁇ 92.5% purity of 64 Cu, ⁇ 93.0% purity of 64 Cu, ⁇ 93.5% purity of 64 Cu, ⁇ 94.0% purity of 64 Cu, ⁇ 94.5% purity of 64 Cu, ⁇ 95.0% purity of 64 Cu, ⁇ 95.5% purity of 64 Cu, ⁇ 96.0% purity of 64 Cu, ⁇ 96.5% purity of 64 Cu, ⁇ 97.0% purity of 64 Cu, ⁇ 97.5% purity of 64 Cu, ⁇ 98.0% purity of 64 Cu ⁇ 98.5% purity of 64 Cu, ⁇ 98.7% purity of 64 Cu, ⁇ 99.0% purity of 64 Cu, ⁇ 99.0% purity of 64 Cu, ⁇ 99.3% purity of 64 Cu, ⁇ 99.5% purity of 64 Cu, ⁇ 99.5% purity
  • the composition may also comprise from 0 to about 14 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 5%, from 0 to about 4.5%, from 0 to about 4.0%, from 0 to about 3.5%, from 0 to about 3.0%, from 0 to about 2.5%, from 0 to about 2.0%, from 0 to about 1.5%, from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, or from 0 to about 0.1% of metals other than 64 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 5%, from 0 to about 4.5%, from 0 to about 4.0%, from 0 to about 3.5%, from 0 to about 3.0%, from 0 to about 2.5%, from 0 to about 2.0%, from 0 to about 1.5%, from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, or from 0 to about 0.1% by weight of the composition of metal contaminants selected from the group consisting of calcium, cobalt, gallium, germanium, copper, gold, iron, lead, mercury, nickel, zinc, and combinations thereof.
  • the composition may also comprise from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, and/or from 0 to about 0.1% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, and/or from 0 to about 0.1% of 67 Cu.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% of 68 Zn by weight of the composition.
  • the composition may also comprise from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, and/or from 0 to about 0.1% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% of any element or isotope with a mass number of 67 or greater by weight of the composition.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% of any element or isotope with a mass number of 68 or greater by weight of the composition.
  • the composition may also comprise from 0 to about 5%, from 0 to about 4.5%, from 0 to about 4.0%, from 0 to about 3.5%, from 0 to about 3.0%, from 0 to about 2.5%, from 0 to about 2.0%, from 0 to about 1.5%, from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, or from 0 to about 0.1% by weight of the composition of radioactive or nonradioactive elements selected from 15 100563663.1 Atty. Docket No.
  • C-US-009 WO1 the group consisting of calcium, cobalt, gallium, germanium, gold, iron, lead, mercury, nickel, zinc, and combinations thereof.
  • the composition comprising 64 Cu may have a total content of trace metals of less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.1 ppm of trace metals, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, gallium, germanium, zinc, and combinations thereof.
  • the composition comprising 64 Cu may have a total content of less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.1 ppm of 67 Cu (e.g., 0 ppm of 67 Cu).
  • the composition comprising 64 Cu may have a total content of less than about 50 ppb, less than about 25 ppb, less than about 10 ppb, less than about 5 ppb, less than about 1 ppb, less than about 0.5 ppb, or less than about 0.1 ppb of 67 Cu (e.g., 0 ppb of 67 Cu).
  • the composition comprising 64 Cu may have a total content of less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.1 ppm of 68 Zn (e.g., 0 ppm of 68 Zn).
  • the composition comprising 64 Cu may have a total content of less than about 50 ppb, less than about 25 ppb, less than about 10 ppb, less than about 5 ppb, less than about 1 ppb, less than about 0.5 ppb, or less than about 0.1 ppb of 68 Zn (e.g., 0 ppb of 68 Zn).
  • the composition comprising 64 Cu may have a total content of less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.1 ppm of any element or isotope with a mass number of 67 or greater.
  • the composition comprising 64 Cu may have a total content of less than about 50 ppb, less than about 25 ppb, less than about 10 ppb, less than about 5 ppb, less than about 1 ppb, less than about 0.5 ppb, or less than about 0.1 ppb of any element or isotope with a mass number of 67 or greater.
  • the composition comprising 64 Cu may have a total content of less than about 25 ppm, less than about 10 ppm, less than about 5 ppm, less than about 1 ppm, less than about 0.5 ppm, or less than about 0.1 ppm of any element or isotope with a mass number of 68 or greater.
  • the composition comprising 64 Cu may have a total content of less than about 50 ppb, less than about 25 ppb, less than about 10 ppb, less than about 5 ppb, less than about 1 ppb, less than about 0.5 ppb, or less than about 0.1 ppb of any element or isotope with a mass number of 68 or greater. 16 100563663.1 Atty. Docket No.
  • the composition may also comprise from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, and/or from 0 to about 0.1% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, and/or from 0 to about 0.1% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% of 68 Zn by weight of the composition.
  • the composition may also comprise from 0 to about 1.0%, from 0 to about 0.7%, from 0 to about 0.5%, from 0 to about 0.3%, and/or from 0 to about 0.1% of 67 Cu by weight of the composition.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% by weight of the composition of any element or isotope with a mass number of 67 or greater.
  • the composition may also comprise from 0 to about 0.01%, from 0 to about 0.005%, from 0 to about 0.001%, or from 0 to about 0.0005% by weight of the composition of any element or isotope with a mass number of 68 or greater.
  • the composition comprising 64 Cu may have a total content of less than or equal to about 10 ⁇ g/mL, less than or equal to about 9 ⁇ g/mL, less than or equal to about 8 ⁇ g/mL, less than or equal to about 7 ⁇ g/mL, less than or equal to about 6 ⁇ g/mL, less than or equal to about 5 ⁇ g/mL, less than or equal to about 4 ⁇ g/mL, less than or equal to about 3 ⁇ g/mL, less than or equal to about 2 ⁇ g/mL, less than or equal to about 1 ⁇ g/mL, or about 0 ⁇ g/mL individually of copper, gold, iron, lead, mercury, nickel, gallium, germanium, and/or zinc.
  • the composition comprising 64 Cu may have a total content of less than or equal to about 10 ⁇ g/mL, less than or equal to about 9 ⁇ g/mL, less than or equal to about 8 ⁇ g/mL, less than or equal to about 7 ⁇ g/mL, less than or equal to about 6 ⁇ g/mL, less than or equal to about 5 ⁇ g/mL, less than or equal to about 4 ⁇ g/mL, less than or equal to about 3 ⁇ g/mL, less than or equal to about 2 ⁇ g/mL, less than or equal to about 1 ⁇ g/mL, or about 0 ⁇ g/mL of 67 Cu.
  • composition comprising 64 Cu may have a total content of less than or equal to about 10 ⁇ g/mL, less than or equal to about 9 ⁇ g/mL, less than or equal to about 8 ⁇ g/mL, less than or equal 17 100563663.1 Atty. Docket No.
  • the composition comprising 64 Cu may have a total content of less than or equal to about 10 ⁇ g/mL, less than or equal to about 9 ⁇ g/mL, less than or equal to about 8 ⁇ g/mL, less than or equal to about 7 ⁇ g/mL, less than or equal to about 6 ⁇ g/mL, less than or equal to about 5 ⁇ g/mL, less than or equal to about 4 ⁇ g/mL, less than or equal to about 3 ⁇ g/mL, less than or equal to about 2 ⁇ g/mL, less than or equal to about 1 ⁇ g/mL, or about 0 ⁇ g/mL of any element or isotope with a mass number of 67 or greater.
  • the composition comprising 64Cu may have a total content of less than or equal to about 10 ⁇ g/mL, less than or equal to about 9 ⁇ g/mL, less than or equal to about 8 ⁇ g/mL, less than or equal to about 7 ⁇ g/mL, less than or equal to about 6 ⁇ g/mL, less than or equal to about 5 ⁇ g/mL, less than or equal to about 4 ⁇ g/mL, less than or equal to about 3 ⁇ g/mL, less than or equal to about 2 ⁇ g/mL, less than or equal to about 1 ⁇ g/mL, or about 0 ⁇ g/mL of any element or isotope with a mass number of 68 or greater.
  • the composition comprising 64Cu may have a total metals content of less than or equal to about 10 ⁇ g/mL, less than or equal to about 9 ⁇ g/mL, less than or equal to about 8 ⁇ g/mL, less than or equal to about 7 ⁇ g/mL, less than or equal to about 6 ⁇ g/mL, less than or equal to about 5 ⁇ g/mL, less than or equal to about 4 ⁇ g/mL, less than or equal to about 3 ⁇ g/mL, less than or equal to about 2 ⁇ g/mL, less than or equal to about 1 ⁇ g/mL, or about 0 ⁇ g/mL for all trace metals combined, wherein the trace metals are selected from the group consisting of copper, gold, iron, lead, mercury, nickel, gallium, germanium, zinc, and combinations thereof.
  • compositions may be characterized as being substantially free from metals other than 64 Cu.
  • the compositions of the present invention may further be characterized as pharmaceutical grade, suitable for human administration, and/or suitable for administration to a human subject in need thereof.
  • the compositions of the present invention may be suitable for administration to a human subject in need thereof once divided into a smaller aliquot.
  • the compositions may comprise from about 2 Ci to about 5 Ci of 64 Cu at EOB, from about 5 Ci to about 9 Ci of 64 Cu at EOB, from about 9 Ci to about 15 Ci at EOB, or from about 15 Ci to about 17 Ci at EOB. In further 18 100563663.1 Atty. Docket No.
  • the compositions may comprise from about 2 Ci to about 5 Ci of 64 Cu (at EOB) after about 2-4 h of bombardment, or about 5 Ci to about 9 Ci of 64 Cu (at EOB) after about 6 h of bombardment, or about 4 Ci to about 15 Ci of 64 Cu (at EOB) after about 8-12 h of bombardment. In other embodiments, the compositions may comprise from about 15 Ci to about 110 Ci or higher of 64 Cu at EOB. [0055] Each of the compositions disclosed herein may be produced during a single cyclotron run and/or may be obtained from a single cyclotron bombardment.
  • a 64 Cu composition production schedule production of a 64 Cu composition begins with the cyclotron bombardment of a target beginning on Day 0 until EOB.
  • the EOB time may range from the afternoon to the evening of Day 0 or even earlier or longer in some instances.
  • the 64 Cu is stripped or removed from the target and processed to form a 64 Cu composition that has a high level of radionuclidic purity.
  • the radionuclidic purity of the 64 Cu composition is typically measured on Day 1, which is referred to as the Raw Material Calibration Time. In some cases, the raw material calibration time may occur about 6:00 am on Day 1.
  • the 64 Cu composition that is produced using the 64 Cu composition is then sent to a location where it is administered to a patient on Day 2.
  • the radionuclidic purity of the 64 Cu compositions disclosed herein is generally greater than about 95.0%, greater than about 96%, greater than about 97.0%, greater than about 98.0%, greater than about 98.5%, greater than about 99%, greater than about 99.5%, or greater than about 99.9% at the Raw Material Calibration Time.
  • short-lived radioisotopes present in the 64 Cu compositions will decay away which causes the radionuclidic purity of the 64 Cu compositions to increase.
  • another calculation of the radionuclidic purity is determined for 64 Cu composition at the Drug Product Calibration Time, which is a set time on Day 2 that occurs shortly before the expiration of the 64 Cu radiopharmaceutical.
  • the Drug Product Calibration Time is calculated for the radionulidic purity of the 64 Cu composition that exists at 5:00 pm on Day 2, the day when the 64 Cu radiopharmaceutical is administered to the patient.
  • the radionuclidic purity of the 64 Cu compositions disclosed herein is generally greater than about greater than about 99%, greater than about 99.5%, greater 19 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 than about 99.7%, greater than about 99.8%, or greater than about 99.9% at the Drug Product Calibration Time.
  • the specific activity of the 64 Cu in the compositions disclosed herein may be greater than 25 mCi 64 Cu/ ⁇ g Cu, greater than 30 mCi 64 Cu/ ⁇ g Cu, greater than 35 mCi 64 Cu/ ⁇ g Cu, greater than 40 mCi 64 Cu/ ⁇ g Cu, greater than 45 mCi 64 Cu/ ⁇ g Cu, greater than 50 mCi 64 Cu/ ⁇ g Cu, greater than 75 mCi 64 Cu/ ⁇ g Cu, or greater than 100 mCi 64 Cu/ ⁇ g Cu at EOB.
  • the specific activity of the 64 Cu in the compositions disclosed herein may be greater than or equal to 3800 mCi 64 Cu/ ⁇ g Cu greater than or equal to 4800 mCi 64 Cu/ ⁇ g Cu, greater than or equal to 5800 mCi 64 Cu/ ⁇ g Cu, or greater than or equal to 6800 mCi 64 Cu/ ⁇ g Cu at EOB.
  • Those skilled in the art understand that the specific activities of the compositions decrease over time.
  • the specific activity may range from about 30 mCi 64 Cu/ ⁇ g Cu to about 100 mCi 64 Cu/ ⁇ g Cu, from about 40 mCi 64 Cu/ ⁇ g Cu to about 100 mCi 64 Cu/ ⁇ g Cu, from about 50 mCi 64 Cu/ ⁇ g Cu to about 200 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 200 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 250 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 300 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 400 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 500 mCi 64 Cu/ ⁇ g Cu, from about 150 mCi 64 Cu/ ⁇ g Cu to about 200 mCi 64 Cu/ ⁇ g Cu, from about
  • the specific activity may range from about 50 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 75 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 125 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 150 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 175 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 200 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 300 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 20 100563663.1 Atty.
  • the specific activity may range from about 50 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 75 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 300 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 350 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 400 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64Cu/ ⁇ g Cu, from about 500 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 750 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu, from about 1000 mCi 64 Cu/ ⁇ g Cu to about 3800 mC
  • the specific activity may range from about 40 64 Cu/ ⁇ g Cu to about 2300 mCi 64 Cu/ ⁇ g Cu. In other embodiments, the specific activity may range from about 50 mCi 64 Cu/ ⁇ g Cu to about 4800 mCi 64 Cu/ ⁇ g Cu, from about 75 mCi 64 Cu/ ⁇ g Cu to about 4800 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 4800 mCi 64 Cu/ ⁇ g Cu, from about 50 mCi 64 Cu/ ⁇ g Cu to about 5800 mCi 64 Cu/ ⁇ g Cu, from about 75 mCi 64 Cu/ ⁇ g Cu to about 5800 mCi 64 Cu/ ⁇ g Cu, from about 100 mCi 64 Cu/ ⁇ g Cu to about 5800 mCi 64 Cu/ ⁇ g Cu, from about 50 mCi 64 Cu/ ⁇ g Cu to about 6800 mCi 64 Cu/ ⁇ g Cu, from about 75 mCi 64 Cu/ ⁇ g Cu to about
  • the specific activity may range from about 40 64 Cu/ ⁇ g Cu to about 500 mCi 64 Cu/ ⁇ g Cu at EOB, from about 500 64 Cu/ ⁇ g Cu to about 1000 mCi 64 Cu/ ⁇ g Cu at EOB, or from about 1000 64 Cu/ ⁇ g Cu to about 2300 mCi 64 Cu/ ⁇ g Cu at EOB.
  • the 64 Cu compositions disclosed herein comprise low levels of metal contaminants.
  • the metal contaminants may be radioactive or nonradioactive.
  • the metal contaminants may include calcium, cobalt, copper, gold, iron, 21 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 lead, mercury, nickel, and zinc.
  • the 2 M HCl eluate described below in Example 5 comprises 0 ppm Au, 0 ppm Hg, ⁇ 0.02 ppm Co, ⁇ 0.2 ppm Fe, ⁇ 0.4 ppm Pb, ⁇ 0.5 ppm Ni, ⁇ 0.6 ppm Cu, and ⁇ 1.5 ppm Zn.
  • the 64 Cu compositions disclosed herein comprise less than about less than about 6 ppm total, less than about 5 ppm total, less than about 4 ppm total, or less than about 3 ppm total of cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.
  • the 64 Cu compositions disclosed herein comprise less than about less than about 6 ppm total, less than about 5 ppm total, less than about 4 ppm total, or less than about 3 ppm total of cobalt, 67 Cu, gold, iron, lead, mercury, nickel, and/or zinc. In general, the 64 Cu compositions disclosed herein comprise less than about less than about 6 ppm total, less than about 5 ppm total, less than about 4 ppm total, or less than about 3 ppm total of 68 Zn.
  • the 64 Cu compositions disclosed herein may comprise less than about less than about 6 ppm total, less than about 5 ppm total, less than about 4 ppm total, less than about 3 ppm total, less than about 2 ppm total, less than about 1 ppm total, or less than about 0.5 ppm total of any element or isotope with a mass number of 67 or greater.
  • the 64 Cu compositions disclosed herein may comprise less than about less than about 6 ppm total, less than about 5 ppm total, less than about 4 ppm total, less than about 3 ppm total, less than about 2 ppm total, less than about 1 ppm total, or less than about 0.5 ppm total of any element or isotope with a mass number of 68 or greater.
  • the 64 Cu compositions disclosed herein may comprise a solution of hydrochloric acid (HCl) such that the solution comprises 64 CuCl2.
  • the solution of HCl may comprise from about 0.005 M to about 3.0 M of HCl.
  • the solution of HCl may comprise HCl at a molarity from about 0.01 M to about 2.0 M, from about 0.02 M to about 1.0 M, or from about 0.04 M to about 0.06 M.
  • the 64 Cu compositions may comprise a solution of about 0.05 M HCl.
  • the compositions disclosed herein may further comprise at least one bifunctional chelating agent such that the copper may complex with the bifunctional chelating agent.
  • the bifunctional chelating agent may be a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.
  • suitable bifunctional chelating agents include 1,4,7,10- tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA), DOTAGA, 1,4,7- 22 100563663.1 Atty. Docket No.
  • the bifunctional chelating agent may be DOTA or DOTAGA.
  • the bifunctional chelating agent may be linked to a cell targeting agent such as a peptide, protein, antibody, or fragment thereof.
  • a cell targeting agent such as a peptide, protein, antibody, or fragment thereof.
  • the processes disclosed herein may be “non-carrier added” in that no inactive material or carrier is intentionally added during the production process.
  • the processes disclosed herein may optionally be “carrier added” in that an inactive material or carrier (e.g., elemental copper) may be intentionally added during the production process.
  • an inactive material or carrier e.g., elemental copper
  • the processes disclosed herein are able to produce 64 Cu in high yield and with high specific activity in one cyclotron run. Stated another way, high yield and high specific activity compositions comprising 64 Cu are obtainable from a single cyclotron target during one cyclotron run. Depending upon the various parameters, yields as high as about 40 Ci to about 110 Ci of 64 Cu may be achieved using the processes disclosed herein.
  • the production process comprises bombarding a 64 Ni target with a proton beam such that 64 Cu is produced, and cobalt-61 ( 61 Co) is produced as a by- product.
  • the next step of the process comprises stripping the metals from the 23 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 bombarded target with a strong acid (e.g., 6 M to about 12.1 M HCl) to form a strip solution.
  • the last step of the production process comprises purifying the 64 Cu by ion exchange chromatography.
  • the ion exchange chromatography process comprises (i) passing the strip solution through a column comprising an ion exchange resin such that 64 Cu binds to the ion exchange resin and 64 Ni passes through the column as a flow- through, (ii) rinsing the column with a volume of HCl having a molarity of about 3 M to about 6 M and (iii) adding a volume of HCl having a molarity of about 0.5 M to about 3 M to the column to elute the 64 Cu from the ion exchange resin and collecting an eluate comprising 64Cu.
  • FIG.1 presents a schematic of an iteration of the process.
  • Suitable cyclotrons include low-energy cyclotrons (e.g., 3-20 MeV energy range) and medium-energy cyclotrons (e.g., 15-30 MeV range).
  • the targets of said cyclotrons may be curved or flat. As detailed in Example 3 below, the present disclosure reveals that cyclotron targets may be bombarded at high currents with approximately 12 MeV to 13 MeV protons. Suitable cyclotrons and cyclotron targets are also described below in Section (III)(a) and Section (IV)(a).
  • the cyclotron target may comprise a copper layer that has been electroplated to a thickness of about 5 ⁇ m to about 10 ⁇ m, about 10 ⁇ m to about 25 ⁇ m, about 25 ⁇ m to about 50 ⁇ m, about 50 ⁇ m to about 75 ⁇ m, or about 75 ⁇ m to about 100 ⁇ m (e.g., on an enriched 64 Ni layer).
  • the cyclotron target may comprise a copper base layer that has been electroplated with gold to a thickness of about 50 ⁇ m.
  • the gold-plated cyclotron target then may be plated with enriched 64 Ni.
  • the 64 Ni may be enriched to about 98%, about 99%, about 99.6%, or about 99.9% 64 Ni.
  • the targeting mass of the plated material may range from about 40 mg to about 800 mg, about 50 mg to about 790 mg, about 60 mg to about 780 mg, about 70 mg to about 770 mg, about 80 mg to about 760 mg, about 90 mg to about 750 mg, about 100 mg to about 740 mg, about 110 mg to about 730 mg, about 120 mg to about 720 mg, about 130 mg to about 710 mg, about 120 mg to about 700 mg, about 110 mg to about 690 mg, 120 mg to about 680 mg, about 130 mg to about 670 mg, about 140 mg to about 660 mg, about 24 100563663.1 Atty. Docket No.
  • the targeting mass of enriched 64 Ni may be about 550 mg, about 551 mg, about 552 mg, about 553 mg, about 554 mg, about 555 mg, about 556 mg, about 557 mg, about 558 mg, about 559 mg, about 600 mg, about 601 mg, about 602 mg, about 603 mg, about 604 mg, about 605 mg, about 606 mg, about 607 mg, about 608 mg, about 609 mg, about 610 mg, about 611 mg, about 612 mg, about 613 mg, about 614 mg, about 615 mg, about 616 mg, about 617 mg, about 618 mg, about 619 mg, about 620 mg, about 621 mg, about 622 mg, about 623 mg, about 624 mg, about 625 mg, about 626 mg, about 627 mg, about 628 mg, about 629 mg, about 630 mg, about 631 mg, about 632 mg, about 633 mg, about 634 mg, about 635 mg, about 636 mg, about 637 mg,
  • the targeting mass is 550-750 mg.
  • the plating area may range from about 3.0 cm 2 to about 25.0 cm 2 , from about 3.5 cm 2 to about 24.5 cm 2 , from about 4.0 cm 2 to about 24.0 cm 2 , from about 4.5 cm 2 to about 23.5 cm 2 , from about 5.0 cm 2 to about 23.0 cm 2 , from about 5.5 cm 2 to about 22.5 cm 2 , from about 6.0 cm 2 to about 22.0 cm 2 , from about 6.5 cm 2 to about 21.5 cm 2 , from about 7.0 cm 2 to about 21.0 cm 2 , from about 7.5 cm 2 to about 20.5 cm 2 , from about 8.0 cm 2 to about 20.0 cm 2 , from about 8.5 cm 2 to about 19.5 cm 2 , from about 9.0 cm 2 to about 19.0 cm 2 , from about 9.5 cm 2 to about 18.5 cm 2 , from about 10.0 cm 2 to about 18.0 cm 2 , from about 10.5 cm 2 to about 17.5 cm 2 , from about 11.0 cm 2
  • the plating area is about 20 cm 2 , 21 cm 2 , 22 cm 2 , 23 cm 2 , 24 cm 2 , or 25 cm 2 . In another example, the plating area is 23 cm 2 and the targeting mass is 550-750 mg.
  • the plated layer of 64 Ni may have a thickness from about 8 ⁇ m to about 20 ⁇ m, from about 10 ⁇ m to about 18 ⁇ m, from about 12 ⁇ m to about 16 ⁇ m, or about 14 ⁇ m. [0071] In the processes disclosed herein, the 64 Ni target area is bombarded with low energy protons to produce 64 Cu.
  • the proton beam of the cyclotron is adjusted to have an energy of less than about 20 MeV, less than about 25 MeV, or less than about 30 MeV on the target.
  • the energy of the proton beam 26 100563663.1 Atty. Docket No.
  • C-US-009 WO1 at the target can range from about 5 MeV to about 20 MeV, about 5 MeV to about 30 MeV, about 10 MeV to about 30 MeV, about 15 MeV to about 30 MeV, from about 7 MeV to about 17 MeV, from about 10 MeV to about 15 MeV, from about 11 MeV to about 14 MeV, from about 10 MeV to about 14 MeV, from about 11 MeV to about 12 MeV, from about 12 MeV to about 13 MeV, from about 15 MeV to about 20 MeV, from about 17 MeV to about 22 MeV, from about 20 MeV to about 25 MeV, from about 22 MeV to about 27 MeV, or from about 25 MeV to about 30 MeV.
  • the actual beam energy at the target is about 12 MeV. In other specific embodiments, the actual beam energy at the target is about 13 MeV.
  • the current of the proton beam may range up to about 1200 ⁇ A. In some embodiments, the current of the proton beam may range from about 10 ⁇ A to about 30 ⁇ A, about 30 ⁇ A to about 100 ⁇ A, from about 100 ⁇ A to about 175 ⁇ A, from about 175 ⁇ A to about 250 ⁇ A, from about 250 ⁇ A to about 300 ⁇ A, from about 300 ⁇ A to about 350 ⁇ A, from about 350 ⁇ A to about 400 ⁇ A, from about 450 ⁇ A to about 500 ⁇ A, from about 550 ⁇ A to about 600 ⁇ A, from about 600 ⁇ A to about 650 ⁇ A, from about 650 ⁇ A to about 700 ⁇ A, from about 700 ⁇ A to about 750 ⁇ A, from about 750 ⁇ A to about 800 ⁇ A, from about 800 ⁇ A
  • the current of the proton beam may be split between two targets or a plurality of targets.
  • the current of the proton beam to each target may range from about 190 ⁇ A to about 230 ⁇ A, from about 200 ⁇ A to about 225 ⁇ A, from about 250 ⁇ A to about 300 ⁇ A, from about 300 ⁇ A to about 350 ⁇ A, or from about 350 ⁇ A to about 410 ⁇ A, from about 405 ⁇ A to about 410 ⁇ A, about 410 ⁇ A to about 420 ⁇ A, about 420 ⁇ A to about 440 ⁇ A, 440 ⁇ A to about 460 ⁇ A, or about 460 ⁇ A to about 480 ⁇ A.
  • the current of the proton beam may be about 300 ⁇ A, about 400 ⁇ A, about 408 ⁇ A, about 410 ⁇ A or about 500 ⁇ A.
  • the proton beam hits the target area at an angle.
  • the angle of the proton beam may range from about 1 ⁇ to about 20 ⁇ , from 27 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 about 2 ⁇ to about 10 ⁇ , from 2 ⁇ to about 8 ⁇ , from about 3 ⁇ to about 6 ⁇ , or about 4 ⁇ .
  • the angle of the proton beam may be tangential to the target area.
  • the target radius of the proton beam may range from about 24 cm to about 32 cm, from about 26 cm to about 30 cm, from about 27 cm to about 29 cm, or about 28 cm. In certain embodiments, the target radius of the proton beam may be about 27.9 cm. In some embodiments, the proton beam may strike about 20-25%, about 15-30%, or about 10-35% of the entire target face. In other embodiments, the total area covered by the beam may range from about 1 cm 2 to about 16 cm 2 , from about 2 cm 2 to about 8 cm 2 , from about 3 cm 2 to about 6 cm 2 , or from about 3.5 cm 2 to about 4.5 cm 2 .
  • the total area covered by the beam may be about 3.0 cm 2 , about 3.5 cm 2 , about 4.0 cm 2 , about 4.5 cm 2 , about 5.0 cm 2 , or about 6.0 cm 2 .
  • the time of bombardment may range from about 0.5 h to about 24 h. In some embodiments, the time of bombardment may range from 0.5 h to about 8 h, from about 8 h to about 16 h, or from about 16 h to about 24 h.
  • the bombardments time may range from 1 h to about 8 h, from about 2 h to about 8 h, from about 4 h to about 8 h, from about 5 h to about 8 h, or about from 5 h to about 7 h. In certain embodiments, the bombardment time may range from about 1 h to about 6 h, from about 2 h to about 6 h, from about 3 h to about 6 h, from about 4 h to about 6 h, or from about be about 5 h to about 6 h.
  • the time of bombardment may be less than 8 h, less than 7.5 h, less than 7 h, less than 6.5 h, less than 6 h, less than 5.5 h, less than 5.0 h, less than 4.5 h, or less than 4 h. In further embodiments, the time of bombardment may be about 1 h, about 2 h, about 3 h, about 4 h, about 5 h, about 6 h, about 7 h, or about 8 h. In specific embodiments, the time of bombardment may range from about 2 h to about 4 h or the time of bombardment may be about 6 h.
  • a cyclotron target comprising 50 mg 64 Ni is bombarded with a proton beam having an energy of about 12 MeV and a beam current of 200 ⁇ A or 225 ⁇ A for about 1 h, 2 h, 3 h, 4 h, or 6 h.
  • a cyclotron target comprising 64 Ni is with a proton beam having an energy of about 13 MeV and a beam current of 150 ⁇ A to 375 ⁇ A, 200 ⁇ A to 375 ⁇ A, 250 ⁇ A to 375 ⁇ A, 275 ⁇ A to 375 ⁇ A, or 300 ⁇ A to 375 ⁇ A, for about 1 h, 2 h, 3 h, 4 h, or 6 h. 28 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 [0077]
  • the bombarded target may comprise from about 2 Ci to about 15 Ci of 64 Cu at the end of bombardment (EOB).
  • the bombarded target also comprises unreacted 64 Ni and 61 Co that is also produced during the bombardment process.
  • the bombarded target may comprise from about 2 Ci to about 3 Ci, from about 3 Ci to about 4 Ci, from about 4 Ci to about 5 Ci, from about 5 Ci to about 6 Ci, from about 6 Ci to about 7 Ci, from about 7 Ci to about 8 Ci, from about 8 Ci to about 9 Ci of 64 Cu, from about 9 Ci to about 10 Ci, from about 10 Ci to about 11 Ci, from about 11 Ci to about 12 Ci, from about 12 to about 13 Ci, from about 13 to about 14 Ci, or from about 14 to about 15 Ci of 64 Cu.
  • the bombarded target may comprise from about 15.0-95.0 Ci, including from about 20.0-85.0 Ci, from about 25.0-80.0 Ci, from about 30.0-75.0 Ci, or from about 40.0-70.0 Ci of 64 Cu.
  • the bombarded target may comprise from about 20.0-95.0 Ci, from about 20.0-90.0 Ci, from about 20.0-85.0 Ci, from about 20.0-80.0 Ci, from about 20.0-75.0 Ci, and from about 20.0-70.0 Ci of 64 Cu.
  • the bombarded target may comprise from about 15.0-25.0 Ci, from about 25.0-35.0 Ci, from about 35.0-45.0 Ci, from about 45.0-55.0 Ci, from about 55.0-65.0 Ci, from about 65.0-75.0 Ci, from about 75.0-85.0 Ci, and from about 85.0-95.0 Ci of 64 Cu.
  • the bombarded target may comprise ⁇ 15 Ci of 64 Cu, ⁇ 17.5 Ci of 64 Cu, ⁇ 20 Ci of 64 Cu, ⁇ 22.5 Ci of 64 Cu, ⁇ 25 Ci of 64 Cu, ⁇ 30 Ci of 64 Cu, ⁇ 35 Ci of 64 Cu, ⁇ 40 of 64 Cu, ⁇ 45 of 64 Cu, ⁇ 50 of 64 Cu, ⁇ 55 of 64 Cu, ⁇ 60 of 64 Cu, ⁇ 65 of 64 Cu, ⁇ 70 of 64 Cu, ⁇ 75 of 64 Cu, ⁇ 80 of 64 Cu, ⁇ 85 of 64 Cu ⁇ ⁇ 90 of 64 Cu, ⁇ 95 of 64 Cu, and/or ⁇ 100 64 Cu.
  • longer bombardment times will yield higher levels of 64 Cu.
  • bombardment times of about 2 h to about 4 h may yield about 2 Ci to about 5 Ci of 64 Cu at EOB
  • bombardment times of about 6 h may yield about 5 Ci to about 9 Ci of 64 Cu at EOB
  • bombardment times of about 12 h may yield about 7 Ci to about 15 Ci of 64 Cu at EOB.
  • Bombardment times of greater than 12 h may yield ⁇ 15 Ci of 64 Cu at EOB, ⁇ 20 Ci of 64 Cu at EOB, and/or ⁇ 25 Ci of 64 Cu at EOB.
  • the processes disclosed herein may produce from about 1 Ci/h to about 1.5 Ci/h of bombardment with proton beam having an energy of about 12 MeV and a current up to about 225 ⁇ A.
  • the incident energy may be optimized to meet the requirements of the desired reaction and minimize unwanted reactions. Bombarding a target with about 29 MeV to about 30 MeV proton (the maximum proton energy of the existing cyclotron) does not yield 64 Cu from 64 Ni. In this specific case, since the maximum reaction probability occurs at approximately 11 MeV, the incident proton energy should be carefully selected such that the proton energy attenuates within the 64 Ni target material to capture the maximum possible production cross section. For example, bombarding an appropriately thick 64 Ni target with 13 MeV protons may allow those protons to attenuate in the material, slowing a portion of them down to 11 MeV where they may have the highest probability of causing the desired nuclear reaction.
  • the target may be cooled using water flow through the target.
  • the water may flow through a series of cooling fins along the length of the target.
  • the target may include 5 to 50, 5 to 10, 10 to 20, 20 to 25, 25 to 30, 30 to 35, 35 to 40, or 40 to 50 cooling fins.
  • the water flow area within the target and cooling fins may range from 40 mm 2 to 45 mm 2 , 45 mm 2 to 50 mm 2 , 50 mm 2 to 55 mm 2 , 55 mm 2 to 60 mm 2 , 60 mm 2 to 65 mm 2 , 65 mm 2 to 70 mm 2 , 70 mm 2 to 75 mm 2 , 75 mm 2 to 80 mm 2 , 80 mm 2 to 85 mm 2 , or 85 mm 2 to 90 mm 2 .
  • the water flow within the target and cooling fins may range from 40 L/min to 90 L/min, 50 L/min to 90 L/min, 55 L/min to 90 L/min, 40 L/min to 50 L/min, 50 L/min to 55 L/min, 55 L/min to 60 L/min, 60 L/min to 65 L/min, 65 L/min to 70 L/min, 70 L/min to 75 L/min, or 75 L/min to 80 L/min, 80 L/min to 85 L/min, or 85 L/min to 90 L/min.
  • the next step of the process comprises stripping the 64 Ni, 64 Cu, 61 Co, and other metals from the bombarded target.
  • the metals are stripped from the target with a strong acid having a pKa of less than 1.
  • Suitable strong acids include hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid.
  • the bombarded target is stripped with HCl having a molarity from about 6 M to about 12.1 M (concentrated HCl).
  • the bombarded target may be stripped with about 6 M HCl, about 7 M HCl, about 8 M HCl, about 9 M HCl, about 10 M HCl, about 11 M HCl, or about 12.1 M HCl.
  • the bombarded target is stripped with about 9 M HCl. 31 100563663.1 Atty. Docket No.
  • the stripping may comprise adding a volume of the strong acid to a chamber or holding vessel comprising the bombarded target, wherein the target is heated to a temperature from about 65 ⁇ C to about 100 ⁇ C. In particular embodiments, the stripping is conducted at a temperature of about 75 ⁇ C. After about 3-5 minutes, the acid may be removed and saved as the first strip solution. The target may be contacted with the strong acid several more times, and the resultant solutions combined with the first strip solution. The chamber holding the target then may be rinsed with the strong acid, and the rinse may be combined with the strip solutions to form the final strip solution.
  • the bombarded target may be exposed three times with about 3 mL of strong acid (e.g., 9 M HCl) to generate a strip solution of approximately 9 mL.
  • the strip solution may be evaporated to dryness or a small volume and the residue may be reconstituted in HCl of the desired molarity (e.g., 9 M) for column chromatography.
  • the stripping comprises contacting the bombarded target with several aliquots of 9 M HCl, at a temperature of about 65 ⁇ C to about 100 ⁇ C, and collecting the aliquots as the strip solution.
  • the chamber holding the bombarded target may be rinsed with 9 M HCl, and the rinse combined with the strip solution.
  • ( c) Purifying 64Cu by ion exchange chromatography [0089] The process further comprises isolating the 64 Cu from the other metals in the strip solution by ion exchange chromatography.
  • the ion exchange chromatography utilizes a strong anion exchange resin. Strong anion exchange resins generally comprise quaternary ammonium groups.
  • a strong anion exchange resin may comprise trialkyl ammonium chloride (e.g., trialkylbenzyl ammonium or trimethylbenzyl ammonium) surface groups or dialkyl 2- hydroxyethyl ammonium chloride (e.g., dimethyl-2-hydroxyethylbenzyl ammonium) surface groups.
  • suitable strong anion exchange resins comprising trimethylbenzyl ammonium groups include AG® 1-X8 (available from Bio-Rad) and 32 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 Dowex® 1X8 resin.
  • the strong anion exchange resin may be AG® 1-X8, 100-200 mesh, chloride form.
  • a variety of columns sizes and bed volumes may be used to purify 64 Cu from the other metals in the strip solution. This process was developed to effectively isolate 64 Cu generated from about 50 mg of 64 Ni target material, using about 4.5 g of strong anion exchange resin in a column having an inner diameter of about 1 cm. It is understood that the amount of strong anion exchange resin may range from about 4.0 g to about 5.0 g and the inner diameter of the column may range from about 0.7 cm to about 1.25 cm without departing from the scope of the disclosure.
  • the volumes of the eluents passed through the column may vary depending upon the size and volume of the column and/or the amount of 64 Ni target material.
  • the ion exchange column is equilibrated with HCl (e.g., 9 M HCl) prior to the chromatography process.
  • Removing 64 Ni the ion exchange separation process comprises passing the strip solution to the prepared ion exchange column, as well as an additional 1 mL of 9 M HCl used to rinse the holding vessel.
  • the strip solution may be added in multiple smaller aliquots (e.g., 3 x 3 mL, 2 x 4.5 mL, etc.) or the strip solution may be added all at once.
  • the Ni in the strip solution does not bind to the strong anion exchange resin and passes through the column, while Cu and Co and other metals bind to the strong anion exchange resin.
  • the column flow through may be collected as a Ni recovery fraction.
  • the column may be rinsed with an additional volume of HCl having the same molarity as that of the strip solution to completely remove any residual Ni from the column.
  • the column may be rinsed with about 10 mL of 9 M HCl.
  • the 10 mL may be added in multiple smaller aliquots (e.g., 5 x 2 mL, 3 x 3.333 mL, etc.) or the 10 mL may be added all at once.
  • the column flow through from the rinse may be collected and combined with the original Ni recovery fraction.
  • the combined Ni recovery fraction may be further processed to recover the 64 Ni, which then may be recycled and used for plating additional cyclotron targets.
  • Nickel recovery processes are well known 33 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 in the art.
  • about 82% of the target 64 Ni present in the strip solution may be recovered from the Ni recovery fraction.
  • the percentage of 64 Ni recovered in the recovery fraction may range from about 40% to about 99% of the starting 64 Ni.
  • the separation process comprises adding the strip solution to the prepared ion exchange column. In this process, the strip solution volume comprises around 20 mL to around 40 mL.
  • the strip solution may be added in multiple smaller aliquots (e.g., 4 x 10 mL, 2 x 10 mL, etc.) or the strip solution may be added all at once.
  • the Ni in the strip solution does not bind to the chromatographic resin and freely passes through the column, while Cu and Co and other metals bind to the ion exchange column.
  • the column flow through volume may be collected as a Ni recovery fraction.
  • the column may be rinsed with an additional volume of HCl having the same molarity as that of the strip solution to completely remove any residual Ni from the column. For example, the column may be rinsed with about 8 mL to about 10 mL of 9 M HCl.
  • the column may be rinsed with about 8 mL of 9 M HCl.
  • the volume of HCl may be added in multiple smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the volume of HCl may be added all at once.
  • the column flow through from the 9 M HCl rinse may be collected and combined with the original Ni recovery fraction.
  • the combined Ni recovery fraction may be further processed to recover the 64 Ni, which then may be recycled and used for plating additional cyclotron targets.
  • Nickel recovery processes are well known in the art. On average, in tracer studies that mimicked a 64 Cu purification, about 98% of the target Ni present in a simulated strip solution may be recovered from the Ni recovery fraction.
  • the percentage of Ni recovered in the recovery fraction may range from about 40% to about 99% of the starting Ni.
  • Removing 61 Co [0095]
  • the ion exchange purification process further comprises adding a volume of HCl having a molarity from about 3 M to about 6 M to the ion exchange column to elute 61 Co (and metals other than Cu).
  • a volume of 3 34 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 M HCl, 4 M HCl, 5 M HCl, or 6 M HCl may be added to the ion exchange column.
  • a volume (e.g., from about 10 mL to about 20 mL) of 4 M HCl may be added to the ion exchange column.
  • a volume e.g., from about 10 mL to about 20 mL
  • 4 M HCl may be added to the column.
  • the eluent may be added in smaller aliquots (e.g., 5 x 2 mL, 3 x 3.33 mL, etc.) or as a bolus or the eluent may be added all at once.
  • the ion exchange column eluate may be collected as a first waste fraction that mainly comprises 61 Co.
  • the ion exchange column may be rinsed with an additional volume (e.g., from about 8 mL to about 10 mL) of NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M to elute residual 61 Co.
  • an additional volume e.g., from about 8 mL to about 10 mL
  • NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M to elute residual 61 Co.
  • a volume (e.g., 8 mL) of 5 M NaCl in 0.05 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the eluent may be added all at once.
  • the ion exchange column eluate from the 5 M NaCl eluent containing 61 Co may be collected and combined with the first waste fraction containing 61 Co.
  • the ion exchange column may be rinsed with an additional volume (e.g., from about 8 mL to about 10 mL) of HCl having a molarity from about 3 M to about 6 M to elute residual 61 Co.
  • a volume (e.g., 8 mL) of 4 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the eluent mL may be added all at once.
  • the ion exchange column eluate from the 5 M HCl eluent containing 61 Co may be collected and combined with first waste fraction containing 61 Co.
  • Isolating 64 Cu [0098]
  • the purification process further comprises adding a volume of HCl having a molarity from about 0.5 M to about 3 M to the ion exchange column to elute the 64 Cu.
  • a volume of 0.5 M HCl, 1 M HCl, 2 M HCl, or 3 M HCl may be added to the ion exchange column.
  • the 64 Cu may be eluted from the ion exchange column with a volume of 2 M HCl. For example, about 8 mL to about 20 mL of 2 M HCl may be added to the column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 4 x 5 mL, etc.) or as a bolus.
  • the eluate comprising 64 Cu is collected as the product of the 35 100563663.1 Atty. Docket No.
  • the purification process further comprises adding a volume of HCl having a molarity from about 0.01 M to about 3 M to the ion exchange column to elute the 64 Cu.
  • a volume of 0.05 M HCl, 1 M HCl, 2 M HCl, or 3 M HCl may be added to the ion exchange column.
  • the 64 Cu may be eluted from the ion exchange column with a volume of 0.05 M HCl.
  • a volume of 0.05 M HCl For example, about 10 mL of 0.05 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 5 x 2 mL, 4 x 2.5 mL, etc.) or the eluent may be added all at once.
  • the eluate comprising 64 Cu is collected as the product of the process.
  • the percentage of 64 Cu recovered in the eluate comprising 64 Cu may range from about 60% to about 100%.
  • the 64 Cu in the eluate exists as 64 CuCl2.
  • the final eluate comprising 64 Cu may be evaporated to dryness (or to a smaller volume) and the resultant residue may be reconstituted in a volume of HCl having a molarity about 0.001 M to about 1 M.
  • the residue may be reconstituted in HCl having a molarity from about 0.005 M to about 0.5 M, from about 0.010 M to about 0.2 M, from about 0.025 M to about 0.1 M, or from about 0.04 M to about 0.06 M.
  • the residue may be reconstituted in 0.05 M HCl to form a final product comprising 64 Cu.
  • the 64 Cu compositions prepared by the processes disclosed herein are described above in section (I).
  • (iv) Exemplary ion exchange chromatography purification process [0102] The 9 M HCl strip solution is passed through the ion exchange column, wherein 64 Cu and 61 Co bind to the resin and 64 Ni flows through the column.
  • the process comprises (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of HCl having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and other metals; and (c) purifying the 64 Cu from the strip solution by chromatography, wherein the chromatography comprises (i) passing the strip solution through an ion exchange resin such that the 64 Cu and 61 Co bind to the ion exchange resin in the column, and 64 Ni passes through as a first flow-through fraction; (ii) rinsing the column with a volume of HCl having a molarity of about 6 M to about 12.1 M to remove residual 64 Ni as a second flow-through fraction; (iii) rinsing the column with a volume of HCl having a molarity of about 3 M to about 6 M to elute
  • Suitable cyclotrons and cyclotron targets are also described above in Section (II)(a) and below in Section (IV)(a).
  • the cyclotron target may comprise a copper base layer that has been electroplated with gold to a thickness of about 50 ⁇ m.
  • the gold-plated cyclotron target then may be plated with enriched 64 Ni.
  • the 64 Ni may be enriched to about 98%, about 99%, about 99.6%, or about 99.9% 64 Ni.
  • the targeting mass of enriched 64 Ni may range from about 675 mg to about 825 mg, from about 700 mg to about 800 mg, from about 720 mg to about 780 mg, or about 750 mg.
  • the plating area may range from about 17.3 cm 2 to about 28.8 cm 2 , from about 18.4 cm 2 to about 37 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 27.6 cm 2 , from about 20.7 cm 2 to about 25.3 cm 2 , from about 21.8 cm 2 to about 24.2 cm2, from about 22.0 cm2 to about 24.0 cm2, or about 23.0 cm2.
  • the plated layer of 64Ni may have a thickness from about 21 ⁇ m to about 53 ⁇ m, from about 26 ⁇ m to about 48 ⁇ m, from about 32 ⁇ m to about 42 ⁇ m, or about 37 ⁇ m.
  • the 64 Ni target area is bombarded with low energy protons to produce 64 Cu.
  • the proton beam of the cyclotron is adjusted to have an energy of less than about 20 MeV on the target.
  • the energy of the proton beam at the target can range from about 5 MeV to about 20 MeV, from about 7 MeV to about 18 MeV, from about 9 MeV to about 16 MeV, from about 10 MeV to about 15 MeV, from about 11 MeV to about 14 MeV, from about 12 MeV to about 13 MeV, or from about 12 MeV to about 14 MeV.
  • the actual beam energy at the target is about 12 MeV.
  • the current of the proton beam may range up to about 408 ⁇ A.
  • the current of the proton beam may range from about 100 ⁇ A to about 150 ⁇ A, from about 150 ⁇ A to about 200 ⁇ A, from about 200 ⁇ A to about 250 ⁇ A, from about 250 ⁇ A to about 300 ⁇ A, from about 300 ⁇ A to about 350 ⁇ A, or from about 350 ⁇ A to about 410 ⁇ A, from about 405 ⁇ A to about 410 ⁇ A, or about 408 ⁇ A.
  • the current of the proton beam may range from about 325 ⁇ A to about 375 ⁇ A, or from about 350 ⁇ A to about 408 ⁇ A.
  • the proton beam hits the target area at an angle.
  • the angle of the proton beam may range from about 1 ⁇ to about 20 ⁇ , from about 2 ⁇ to about 10 ⁇ , from 2 ⁇ to about 8 ⁇ , from about 3 ⁇ to about 6 ⁇ , or about 5 ⁇ .
  • the angle of the proton beam may be tangential to the target area.
  • the beam strike has an elliptic shape with minor and major axes. The minor axes may range from about 25.8 mm to about 34.2 mm, from about 27.9 mm to about 32.1 mm, from about 28.8 mm to about 31.2 mm, or about 30.0 mm.
  • the major axes may range from about 84.4 mm to about 63.6 mm, from about 79.2 mm to about 68.8 mm, from about 77.0 mm to about 71.0 mm, or about 74.0 mm.
  • the minor and major axis of the elliptic beam strike may be about 30.0 mm and 74.0 mm, respectively.
  • the proton beam may strike about 70-80%, about 60-90%, or about 55-95% of the entire target face. In 38 100563663.1 Atty. Docket No.
  • the total area covered by the beam may range from about 14.0 cm 2 to about 30.0 cm 2 , from about 28.0 cm 2 to about 16.0 cm 2 , from about 26.0 cm 2 to about 18.0 cm 2 , or from about 25.0 cm 2 to about 20.0 cm 2 , or 23.0 cm 2 .
  • the time of bombardment may range from about 0.5 h to about 24 h. In some embodiments, the time of bombardment may range from 0.5 h to about 8 h, from about 8 h to about 20 h, or from about 20 h to about 24 h.
  • the bombardment time may range from 1 h to about 24 h, from about 2 h to about 24 h, from about 4 h to about 24 h, from about 5 h to about 24 h, or about from 5 h to about 23 h. In certain embodiments, the bombardment time may range from about 1 h to about 19 h, from about 2 h to about 19 h, from about 3 h to about 19 h, from about 4 h to about 19 h, or from about 5 h to about 19 h.
  • the time of bombardment may be less than 19 h, less than 18 h, less than 17.5 h, less than 17 h, less than 16.5 h, less than 16 h, less than 15.5 h, or less than 15 h. In further embodiments, the time of bombardment may be about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, or about 15 h. In specific embodiments, the time of bombardment may range from about 1 h to about 12 h or the time of bombardment may be about 12 h.
  • a target comprising about 750 mg 64 Ni may be bombarded with a proton beam having an energy of about 10 MeV to about 20 MeV, about 11 MeV to about 18 MeV, or about 12 MeV to about 14 MeV and a beam current of 300 ⁇ A to about 350 ⁇ A, about 350 ⁇ A to about 408 ⁇ A, about 400 ⁇ A to about 450 ⁇ A, about 450 ⁇ A to about 500 ⁇ A, or 500+ ⁇ A for about 10 h, 12 h, 14 h, 16 h, or 19 h.
  • a plurality of targets comprising about 750 mg 64 Ni per target may be bombarded with a proton beam having an energy of about 10 MeV to about 20 MeV, about 11 MeV to about 18 MeV, or about 12 MeV to about 14 MeV and a beam current of 300 ⁇ A to about 350 ⁇ A, about 350 ⁇ A to about 408 ⁇ A, about 400 ⁇ A to about 450 ⁇ A, about 450 ⁇ A to about 500 ⁇ A, or 500+ ⁇ A per target for about 10 h, 12 h, 14 h, 16 h, or 19 h.
  • two targets each comprising about 750 mg 64 Ni may be bombarded simultaneously with a proton beam having an energy of about 12 MeV to about 14 MeV and a beam current, incident on each target, of about 350 ⁇ A to about 408 ⁇ A for about 10 h, 12 h, 14 h, or 19 h. 39 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 [0111]
  • the bombarded target may comprise from about 58 Ci to about 80 Ci of 64 Cu at the end of bombardment (EOB).
  • the bombarded target also comprises unreacted 64 Ni and 61 Co that are produced during the bombardment process.
  • the bombarded target may comprise from about 38 Ci to about 52 Ci, from about 43 Ci to about 59 Ci, from about 48 Ci to about 66 Ci, from about 52 Ci to about 72 Ci, from about 56 Ci to about 77 Ci, from about 58 Ci to about 80 Ci of 64 Cu, from about 60 Ci to about 150 Ci of 64 Cu, or from about 60 Ci to about 200 Ci of 64 Cu, or greater than 200 Ci of 64 Cu
  • longer bombardment times will yield higher levels of 64 Cu. For example, bombardment times of about 12 h to about 16 h may yield about 43 Ci to about 72 Ci of 64 Cu at EOB, and bombardments times of about 19 h may yield about 58 Ci to about 80 Ci of 64 Cu at EOB.
  • the processes disclosed herein may produce from about 3.3 Ci/h to about 3.8 Ci/h of bombardment with proton beam having an energy of about 13 MeV and a current of about 350 ⁇ A or about 408 ⁇ A.
  • the next step of the process comprises stripping metals from the bombarded target.
  • the metals are stripped from the target with a strong acid having a pKa of less than 1. Suitable strong acids include hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid.
  • the bombarded target is stripped with HCl having a molarity from about 6 M to about 12.1 M.
  • the bombarded target may be stripped with about 6 M HCl, about 7 M HCl, about 8 M HCl, about 9 M HCl, about 10 M HCl, about 11 M HCl, or about 12.1 M HCl.
  • the bombarded target is stripped with about 9 M HCl.
  • the stripping may comprise adding a volume of the strong acid to a chamber or holding vessel comprising the bombarded target, wherein the target is heated to a temperature from about 65 °C to about 100 °C. In particular embodiments, the stripping is conducted at a temperature of about 75 °C. After about 3-5 minutes, the acid may be removed and saved as the first strip solution.
  • the target may be contacted with the strong acid several more times, and the resultant solutions combined with the first strip solution.
  • the chamber holding the target then may be rinsed with the strong 40 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 acid, and the rinse may be combined with the strip solutions to form the final strip solution.
  • the bombarded target and the holding chamber may be contacted several times with aliquots (e.g., 5-10 mL) of the strong acid (e.g., HCl) to generate a final strip solution of approximately 20 mL to 40 mL.
  • the stripping comprises contacting the bombarded target with several aliquots of 9 M HCl, at a temperature of about 65 ⁇ C to about 100 ⁇ C, and collecting the aliquots as the strip solution.
  • the chamber holding the bombarded target may be rinsed with 9 M HCl, and the rinse combined with the strip solution.
  • the strip solution comprises 64 Ni, 64 Cu, 61 Co, and can contain other metals (e.g., Fe).
  • Purifying 64Cu by ion exchange chromatography [0115]
  • the last step of the process comprises purifying 64 Cu from the other metals in the strip solution by chromatography.
  • the process comprises passing the strip solution through a packed ion exchange resin bed using a controlled flow rate.
  • the ion exchange column comprises a weak anion exchange resin.
  • Weak anion exchange resins generally comprise polystyrene or polyacrylic ester frames that contain a primary, secondary, or tertiary amino group as the functional group.
  • Suitable weak anionic functional groups include diethyl aminoethyl (DEAE) and dimethyl aminoethyl (DMAE).
  • Examples of suitable weak anion exchange resins comprising 41 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 tertiary ammonium groups include AmberLite ⁇ FPA53 (available from Dupont) and TrisKem TK201 resin.
  • the weak anion exchange resin is TK201 resin, 50-100 micron, and in the chloride form.
  • a variety of column sizes and bed volumes may be used to purify 64 Cu from the other metals in the strip solution. This process was developed to effectively isolate 64 Cu generated from about 750 mg of 64 Ni target material, using a weak anion exchange resin.
  • the column uses about 2.7 g of weak anion exchange resin in a column having an inner diameter of about 1 cm. It is understood that the amount of weak anion exchange resin may range from about 2.4 g to about 3.0 g and the inner diameter of the column may range from about 0.7 cm to about 1.25 cm without departing from the scope of the disclosure.
  • the volumes of the eluents passed through the column may vary depending upon the size and volume of the column and/or the amount of 64 Ni target material.
  • the column ion exchange resin is equilibrated with HCl (e.g., 9 M HCl) prior to the chromatography process.
  • HCl e.g. 9 M HCl
  • the packed resin requires a controlled, pressure generated flow.
  • the 50-100 micron resin bead size equates to roughly 140-270 mesh (as compared to the 100-200 mesh AG® 1-X8 resin) which requires a force greater than gravitational to permit flow.
  • the strip solution volume comprises around 20 mL to around 40 mL.
  • the strip solution may be added in multiple smaller 42 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 aliquots (e.g., 4 x 10 mL, 2 x 10 mL, etc.) or the strip solution may be added all at once.
  • the Ni in the strip solution does not bind to the chromatographic resin and freely passes through the column, while Cu and Co and other metals bind to the ion exchange column.
  • the column flow through volume may be collected as a Ni recovery fraction.
  • the column may be rinsed with an additional volume of HCl having the same molarity as that of the strip solution to completely remove any residual Ni from the column.
  • the column may be rinsed with about 8 mL to about 10 mL of 9 M HCl.
  • the column may be rinsed with about 8 mL of 9 M HCl.
  • the volume of HCl may be added in multiple smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the volume of HCl may be added all at once.
  • the column flow through from the 9 M HCl rinse may be collected and combined with the original Ni recovery fraction.
  • the combined Ni recovery fraction may be further processed to recover the 64 Ni, which then may be recycled and used for plating additional cyclotron targets.
  • Nickel recovery processes are well known in the art. On average, in tracer studies that mimicked a 64 Cu purification, about 98% of the target Ni present in a simulated strip solution may be recovered from the Ni recovery fraction. In various embodiments, the percentage of Ni recovered in the recovery fraction may range from about 40% to about 99% of the starting Ni.
  • Removing 61 Co [0121]
  • the separation process further comprises adding a volume of HCl having a molarity from about 3 M to about 6 M to the column comprising the ion exchange resin to elute 61 Co (and metals other than Cu).
  • a volume of 3 M HCl, 4 M HCl, 5 M HCl, or 6 M HCl may be added to the ion exchange column.
  • a volume (e.g., from about 10 mL to about 20 mL) of 4 M HCl may be added to the ion exchange column.
  • about 10 mL of 4 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 5 x 2 mL, 3 x 3.33 mL, etc.) or the eluent may be added all at once.
  • the ion exchange column eluate may be collected as a first waste fraction that mainly comprises 61 Co. 43 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 [0122]
  • the ion exchange column may be rinsed with an additional volume (e.g., from about 8 mL to about 10 mL) of NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M to elute residual 61 Co.
  • a volume (e.g., 8 mL) of 5 M NaCl in 0.05 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the eluent may be added all at once.
  • the ion exchange column eluate from the 5 M NaCl eluent containing 61 Co may be collected and combined with the first waste fraction containing 61 Co.
  • the ion exchange column may be rinsed with an additional volume (e.g., from about 8 mL to about 10 mL) of HCl having a molarity from about 3 M to about 6 M to elute residual 61 Co.
  • a volume (e.g., 8 mL) of 4 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the eluent mL may be added all at once.
  • the ion exchange column eluate from the 5 M HCl eluent containing 61 Co may be collected and combined with first waste fraction containing 61 Co.
  • Isolating 64 Cu [0124]
  • the separation process further comprises adding a volume of HCl having a molarity from about 0.01 M to about 3 M to the ion exchange column to elute the 64 Cu.
  • a volume of 0.05 M HCl, 1 M HCl, 2 M HCl, or 3 M HCl may be added to the ion exchange column.
  • the 64 Cu may be eluted from the ion exchange column with a volume of 0.05 M HCl.
  • a volume of 0.05 M HCl For example, about 10 mL of 0.05 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 5 x 2 mL, 4 x 2.5 mL, etc.) or the eluent may be added all at once.
  • the eluate comprising 64 Cu is collected as the product of the process.
  • the percentage of 64 Cu recovered in the eluate comprising 64 Cu may range from about 60% to about 100%.
  • the 64 Cu in the eluate exists as 64 CuCl2.
  • the final eluate comprising 64 Cu may be evaporated to dryness (or to a smaller volume) and the resultant residue may be reconstituted in a volume of HCl 44 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 having a molarity about 0.001 M to about 1 M.
  • the residue may be reconstituted in HCl having a molarity from about 0.005 M to about 0.5 M, from about 0.010 M to about 0.2 M, from about 0.025 M to about 0.1 M, or from about 0.04 M to about 0.06 M.
  • the residue may be reconstituted in 0.05 M HCl to form a final product comprising 64 Cu.
  • the 64 Cu compositions prepared by this process are described above in section (I).
  • the process comprises (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of HCl having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and other metals; and (c) purifying the 64 Cu from the strip solution by chromatography, wherein the chromatography comprises (i) passing the strip solution through a first column comprising an extraction resin connected in series to a second column comprising an ion exchange resin such that the one or more metals (e.g., cationic iron) binds to the extraction resin in the first column, the 64 Cu and 61 Co bind to the ion exchange resin in the second column, and 64 Ni passes through both columns as a first flow-through fraction; (ii) rinsing the first and second columns with a volume of HCl having a molarity of about 6 M to about 12.1
  • FIGs.2A, 2B, and 2C present schematics or several embodiments of the dual chromatography purification process.
  • Suitable cyclotrons and cyclotron targets are also described above in Section (II)(a) and Section (III)(a).
  • the cyclotron target may comprise a copper base layer that has been electroplated with gold to a thickness of about 50 ⁇ m.
  • the gold- plated cyclotron target then may be plated with enriched 64 Ni.
  • the 64 Ni may be enriched to about 98%, about 99%, about 99.6%, or about 99.9% 64 Ni.
  • the targeting mass of enriched 64 Ni may range from about 675 mg to about 825 mg, from about 700 mg to about 800 mg, from about 720 mg to about 780 mg, or about 750 mg.
  • the plating area may range from about 17.3 cm 2 to about 28.8 cm 2 , from about 18.4 cm 2 to about 27.6 cm 2 , from about 20.7 cm 2 to about 25.3 cm 2 , from about 21.8 cm 2 to about 24.2 cm 2 , from about 22.0 cm 2 to about 24.0 cm 2, or about 23.0 cm 2 .
  • the plated layer of 64 Ni may have a thickness from about 21 ⁇ m to about 53 ⁇ m, from about 26 ⁇ m to about 48 ⁇ m, from about 32 ⁇ m to about 42 ⁇ m, or about 37 ⁇ m.
  • the 64 Ni target area is bombarded with low energy protons to produce 64 Cu.
  • the proton beam of the cyclotron is adjusted to have an energy of less than about 20 MeV on the target.
  • the energy of the proton beam at the target can range from about 5 MeV to about 20 MeV, about 5 MeV to about 30 MeV, about 10 MeV to about 30 MeV, about 15 MeV to about 30 MeV, from about 7 MeV to about 18 MeV, from about 9 MeV to about 16 MeV, from about 10 MeV to about 15 MeV, from about 11 MeV to about 14 MeV, from about 12 MeV to about 13 MeV, from about 12 MeV to about 14 MeV, from about 15 MeV to about 20 MeV, from about 17 MeV to about 22 MeV, from about 20 MeV to about 25 MeV, from about 22 MeV to about 27 MeV, or from about 25 MeV to about 30 MeV.
  • the actual beam energy at the target is about 12 MeV or about 13 MeV.
  • the current of the proton beam may range up to about 125 ⁇ A to about 200 ⁇ A , about 200 ⁇ A to about 300 ⁇ A, about 300 ⁇ A to about 700 ⁇ A, 350 ⁇ A to about 700 ⁇ A, 400 ⁇ A to about 700 ⁇ A, 450 ⁇ A to about 700 ⁇ A, 500 ⁇ A to about 700 46 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 ⁇ A.
  • the current of the proton beam may range up to 400 ⁇ A, up to 500 ⁇ A, up to 600 ⁇ A, up to 700 ⁇ A, up to 800 ⁇ A, up to 900 ⁇ A, up to 960 ⁇ A, or up to 1200 ⁇ A.
  • the current of the proton beam may be split between two targets or a plurality of targets.
  • the current of the proton beam for each target may be up to about 408 ⁇ A.
  • the current of the proton beam for each target may range from about 100 ⁇ A to about 150 ⁇ A, from about 150 ⁇ A to about 200 ⁇ A, from about 200 ⁇ A to about 250 ⁇ A, from about 250 ⁇ A to about 300 ⁇ A, from about 300 ⁇ A to about 350 ⁇ A, or from about 350 ⁇ A to about 410 ⁇ A, from about 405 ⁇ A to about 410 ⁇ A, about 410 ⁇ A to about 420 ⁇ A, about 420 ⁇ A to about 440 ⁇ A, 440 ⁇ A to about 460 ⁇ A, or about 460 ⁇ A to about 480 ⁇ A.
  • the current of the proton beam may range from about 325 ⁇ A to about 375 ⁇ A, or from about 350 ⁇ A to about 408 ⁇ A.
  • the proton beam hits the target area at an angle.
  • the angle of the proton beam may range from about 1 ⁇ to about 20 ⁇ , from about 2 ⁇ to about 10 ⁇ , from 2 ⁇ to about 8 ⁇ , from about 3 ⁇ to about 6 ⁇ , or about 5 ⁇ .
  • the angle of the proton beam may be tangential to the target area.
  • the beam strike has an elliptic shape with minor and major axes.
  • the minor axes may range from about 25.8 mm to about 34.2 mm, from about 27.9 mm to about 32.1 mm, from about 28.8 mm to about 31.2 mm, or about 30.0 mm.
  • the major axes may range from about 84.4 mm to about 63.6 mm, from about 79.2 mm to about 68.8 mm, from about 77.0 mm to about 71.0 mm, or about 74.0 mm.
  • the minor and major axis of the elliptic beam strike may be about 30.0 mm and 74.0 mm, respectively.
  • the proton beam may strike about 70-80%, about 60-90%, or about 55-95% of the entire target face.
  • the total area covered by the beam may range from about 14.0 cm 2 to about 30.0 cm 2 , from about 28.0 cm 2 to about 16.0 cm 2 , from about 26.0 cm 2 to about 18.0 cm 2 , or from about 25.0 cm 2 to about 20.0 cm 2 , or about 23.0 cm 2 .
  • the time of bombardment may range from about 0.5 h to about 24 h. In some embodiments, the time of bombardment may range from 0.5 h to about 8 h, from about 8 h to about 20 h, or from about 20 h to about 24 h. In other embodiments, the bombardment time may range from about 1 h to about 24 h, from about 2 h to about 47 100563663.1 Atty.
  • the bombardment time may range from about 1 h to about 19 h, from about 2 h to about 19 h, from about 3 h to about 19 h, from about 4 h to about 19 h, or from about 5 h to about 19 h.
  • the time of bombardment may be less than 19 h, less than 18 h, less than 17.5 h, less than 17 h, less than 16.5 h, less than 16 h, less than 15.5 h, or less than 15 h. In further embodiments, the time of bombardment may be about 8 h, about 9 h, about 10 h, about 11 h, about 12 h, about 13 h, about 14 h, or about 15 h. In specific embodiments, the time of bombardment may range from about 1 h to about 12 h or the time of bombardment may be about 12 h.
  • a target comprising about 750 mg 64 Ni may be bombarded with a proton beam having an energy of about 12 MeV to about 14 MeV and a beam current of about 350 ⁇ A to about 408 ⁇ A for about 10 h, 12 h, 14 h, 16 h, or 19 h.
  • two targets each comprising about 750 mg 64 Ni may be bombarded simultaneously with a proton beam having an energy of about 12 MeV to about 14 MeV and a beam current, incident on each target, of about 350 ⁇ A to about 408 ⁇ A for about 10 h, 12 h, 14 h, or 19 h.
  • the bombarded target may comprise from about 58 Ci to about 80 Ci of 64 Cu at the end of bombardment (EOB).
  • the bombarded target also comprises unreacted 64 Ni and 61 Co that are produced during the bombardment process.
  • the bombarded target may comprise from about 38 Ci to about 52 Ci, from about 43 Ci to about 59 Ci, from about 48 Ci to about 66 Ci, from about 52 Ci to about 72 Ci, from about 56 Ci to about 77 Ci, from about 58 Ci to about 80 Ci of 64 Cu, from about 60 Ci to about 150 Ci of 64 Cu, or from about 60 Ci to about 200 Ci of 64 Cu, or greater than 200 Ci of 64 Cu. In general, longer bombardment times will yield higher levels of 64 Cu.
  • bombardment times of about 12 h to about 16 h may yield about 43 Ci to about 72 Ci of 64 Cu at EOB, and bombardments times of about 19 h may yield about 58 Ci to about 80 Ci of 64 Cu at EOB.
  • the processes disclosed herein may produce from about 3.3 Ci/h to about 3.8 Ci/h of bombardment with proton beam having an energy of about 13 MeV and a current of about 350 ⁇ A or about 408 ⁇ A. 48 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 ( b) Stripping the bombarded target [0136]
  • the next step of the process comprises stripping metals from the bombarded target.
  • the metals are stripped from the target with a strong acid having a pKa of less than 1.
  • Suitable strong acids include hydrochloric acid, nitric acid, hydrobromic acid, and sulfuric acid.
  • the bombarded target is stripped with HCl having a molarity from about 6 M to about 12.1 M.
  • the bombarded target may be stripped with about 6 M HCl, about 7 M HCl, about 8 M HCl, about 9 M HCl, about 10 M HCl, about 11 M HCl, or about 12.1 M HCl.
  • the bombarded target is stripped with about 9 M HCl.
  • the stripping may comprise adding a volume of the strong acid to a chamber or holding vessel comprising the bombarded target, wherein the target is heated to a temperature from about 65 °C to about 100 °C. In particular embodiments, the stripping is conducted at a temperature of about 75 °C. After about 3-5 minutes, the acid may be removed and saved as the first strip solution. The target may be contacted with the strong acid several more times, and the resultant solutions combined with the first strip solution. The chamber holding the target then may be rinsed with the strong acid, and the rinse may be combined with the strip solutions to form the final strip solution.
  • the bombarded target and the holding chamber may be contacted several times with aliquots (e.g., 5-10 mL) of the strong acid (e.g., HCl) to generate a final strip solution of approximately 20 mL to 40 mL.
  • the stripping comprises contacting the bombarded target with several aliquots of 9 M HCl, at a temperature of about 65 ⁇ C to about 100 ⁇ C, and collecting the aliquots as the strip solution.
  • the chamber holding the bombarded target may be rinsed with 9 M HCl, and the rinse combined with the strip solution.
  • the strip solution comprises 64 Ni, 64 Cu, 61 Co, and can contain other metals (e.g., Fe).
  • Suitable extraction chromatography extractants include tributylphosphate (TBP), carbamoyl-methylphosphine oxide (CMPO), di-(2-ethylhexyl)- phosphoric acid (D2EHPA), and dipentyl pentylphosphonate (DP[PP]).
  • TBP tributylphosphate
  • CMPO carbamoyl-methylphosphine oxide
  • D2EHPA di-(2-ethylhexyl)- phosphoric acid
  • DP[PP] dipentyl pentylphosphonate
  • the extraction chromatography extractant may be a mixture of CMPO and TBP (e.g., TRU resin; TrisKem).
  • TBP e.g., TRU resin
  • TrisKem e.g., TRU resin
  • TBP TrisKem
  • the extraction resin may be TBP resin, 100-150 mesh, and in the chloride form.
  • the ion exchange column comprises a weak anion exchange resin.
  • Weak anion exchange resins generally comprise polystyrene or polyacrylic ester frames that contain a primary, secondary, or tertiary amino group as the functional group.
  • Suitable weak anionic functional groups include diethyl aminoethyl (DEAE) and dimethyl aminoethyl (DMAE).
  • suitable weak anion exchange resins comprising tertiary ammonium groups include AmberLite ⁇ FPA53 (available from Dupont) and TrisKem TK201 resin.
  • the weak anion exchange resin is TK201 resin, 50-100 mesh, and in the chloride form.
  • a variety of columns sizes and bed volumes may be used to purify 64 Cu from the other metals in the strip solution. This process was developed to effectively isolate 64 Cu generated from about 750 mg of 64 Ni target material, using two distinct columns, containing extraction and weak anion exchange resins, connected in series.
  • the first column comprises about 300 mg of extraction resin in a column having an inner diameter of 0.5 cm. It is understood that the amount of extraction resin may 50 100563663.1 Atty. Docket No.
  • C-US-009 WO1 range from about 270 mg to about 330 mg and the inner diameter of the column may range from about 0.4 cm to about 0.6 cm without departing from the scope of the disclosure.
  • the second column uses about 2.7 g of weak anion exchange resin in a column having an inner diameter of about 1 cm. It is understood that the amount of weak anion exchange resin may range from about 2.4 g to about 3.0 g and the inner diameter of the column may range from about 0.7 cm to about 1.25 cm without departing from the scope of the disclosure.
  • the volumes of the eluents passed through the column may vary depending upon the size and volume of the column and/or the amount of 64 Ni target material.
  • the columns containing extraction resin and ion exchange resin are equilibrated with HCl (e.g., 9 M HCl) prior to the chromatography process.
  • HCl e.g. 9 M HCl
  • the separation process comprises adding the strip solution to the prepared extraction column connected in series to the prepared ion exchange column.
  • the strip solution volume comprises around 20 mL to around 40 mL.
  • the strip solution may be added in multiple smaller aliquots (e.g., 4 x 10 mL, 2 x 10 mL, etc.) or the strip solution may be added all at once.
  • the Fe in the strip solution binds to the extractant (e.g., TBP) in the first column.
  • the Ni in the strip solution does not bind to the chromatographic resins and freely passes through both columns, while Cu and Co and other metals bind to the ion exchange column.
  • the columns flow through volume may be collected as a Ni recovery fraction.
  • the columns may be rinsed with an additional volume of HCl having the same molarity as that of the strip solution to completely remove any residual Ni from the columns. For example, the columns may be rinsed with about 8 mL to about 10 mL of 9 M HCl. For example, the columns may be rinsed with about 8 mL of 9 M HCl.
  • the volume of HCl may be added in multiple smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the volume of HCl may be added all at once.
  • the column flow through from the 9 M HCl rinse may be collected and combined with the original Ni recovery fraction.
  • the combined Ni recovery fraction may be further processed to recover the 64 Ni, which then may be recycled and used for plating additional cyclotron targets.
  • Nickel recovery 51 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 processes are well known in the art.
  • the separation process further comprises adding a volume of HCl having a molarity from about 3 M to about 6 M to the second column comprising the ion exchange resin to elute 61 Co (and metals other than Cu). In various embodiments, a volume of 3 M HCl, 4 M HCl, 5 M HCl, or 6 M HCl may be added to the ion exchange column.
  • a volume (e.g., from about 10 mL to about 20 mL) of 4 M HCl may be added to the ion exchange column.
  • a volume e.g., from about 10 mL to about 20 mL
  • 4 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 5 x 2 mL, 3 x 3.33 mL, etc.) or the eluent may be added all at once.
  • the ion exchange column eluate may be collected as a first waste fraction that mainly comprises 61 Co.
  • the ion exchange column may be rinsed with an additional volume (e.g., from about 8 mL to about 10 mL) of NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M to elute residual 61 Co.
  • an additional volume e.g., from about 8 mL to about 10 mL
  • NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M to elute residual 61 Co.
  • a volume (e.g., 8 mL) of 5 M NaCl in 0.05 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the eluent may be added all at once.
  • the ion exchange column eluate from the 5 M NaCl eluent containing 61 Co may be collected and combined with the first waste fraction containing 61 Co.
  • the ion exchange column may be rinsed with an additional volume (e.g., from about 8 mL to about 10 mL) of HCl having a molarity from about 3 M to about 6 M to elute residual 61 Co.
  • an additional volume e.g., from about 8 mL to about 10 mL
  • a volume (e.g., 8 mL) of 4 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 4 x 2 mL, 2 x 4 mL, etc.) or the eluent mL may be added all at 52 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 once.
  • the ion exchange column eluate from the 5 M HCl eluent containing 61 Co may be collected and combined with first waste fraction containing 61 Co.
  • Isolating 64 Cu [0148]
  • the separation process further comprises adding a volume of HCl having a molarity from about 0.01 M to about 3 M to the ion exchange column to elute the 64 Cu.
  • a volume of 0.05 M HCl, 1 M HCl, 2 M HCl, or 3 M HCl may be added to the ion exchange column.
  • the 64 Cu may be eluted from the ion exchange column with a volume of 0.05 M HCl.
  • a volume of 0.05 M HCl For example, about 10 mL of 0.05 M HCl may be added to the ion exchange column.
  • the eluent may be added in smaller aliquots (e.g., 5 x 2 mL, 4 x 2.5 mL, etc.) or the eluent may be added all at once.
  • the eluate comprising 64 Cu is collected as the product of the process.
  • the percentage of 64 Cu recovered in the eluate comprising 64 Cu may range from about 60% to about 100%.
  • the 64 Cu in the eluate exists as 64 CuCl2.
  • the final eluate comprising 64 Cu may be evaporated to dryness (or to a smaller volume) and the resultant residue may be reconstituted in a volume of HCl having a molarity about 0.001 M to about 1 M.
  • the residue may be reconstituted in HCl having a molarity from about 0.005 M to about 0.5 M, from about 0.010 M to about 0.2 M, from about 0.025 M to about 0.1 M, or from about 0.04 M to about 0.06 M.
  • the residue may be reconstituted in 0.05 M HCl to form a final product comprising 64 Cu.
  • the 64 Cu compositions prepared by this process are described above in section (I).
  • Exemplary extraction and ion exchange chromatography purification process [0151] The 9 M HCl strip solution is passed through a first column comprising an extraction resin connected in series with a second column comprising a weak anion exchange resin.
  • the Fe in the strip solution binds to the extraction resin in the first 53 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 column, 64 Cu and 61 Co bind to the ion exchange resin in the second column, and 64 Ni flows through both columns.
  • the first and second columns are rinsed with 9 M HCl to remove residual 64 Ni.
  • the initial column flow through and the 9 M HCL rinse can be combined as the Ni recovery fraction.
  • the ion exchange column is rinsed with 4 M HCl to elute the 61 Co and then with 5 M NaCl in 0.05 M HCl or additional 4 M HCl to elute residual 61 Co.
  • the present disclosure also includes a process for improving the consistency of the radiochemical purity (RCP) of radiopharmaceutical compositions comprising 64 Cu coordinated to a targeting ligand through an attached chelating group.
  • Elemental copper non-radioactive copper
  • Improvements in target robustness and cyclotron optimization have reduced the level of elemental copper in the radiopharmaceutical composition comprising 64 Cu radiopharmaceuticals.
  • RCP may be affected by the presence of elemental copper in the radiopharmaceutical product.
  • the RCP began to diminish as the bombardment process improved and reduced the concentration of elemental copper present in the purified 64 CuCl2 product.
  • Adding elemental copper to the purified 64 CuCl2 product used to label some ligands was found to improve the RCP of the resulting labeled radiopharmaceutical.
  • elemental or non-radioactive copper may be added to the reaction mixture comprising the 64 Cu eluate used to make the 64 Cu radiopharmaceutical composition.
  • the final radiopharmaceutical composition may include from at least about 0.1 ppm to about 5 ppm of elemental copper, about 1 ppm to about 5 ppm of elemental copper, about 2.5 ppm to about 7.5 ppm of elemental copper, about 5 ppm to about 10 ppm of elemental copper, about 5 ppm to about 30 ppm of 54 100563663.1 Atty. Docket No.
  • the final radiopharmaceutical composition may include 1 ppm to 75 ppm, 2 ppm to 60 ppm, 5 ppm to 50 ppm, 10 ppm to 40 ppm, or 20 ppm to 30 ppm of elemental copper.
  • the final radiopharmaceutical composition (and the elemental copper) may be in an injectable solution form.
  • the eluate comprising 64 Cu may be reconstituted in 0.05 M HCl.
  • the process of spiking the final radiopharmaceutical composition with elemental copper includes (i) preparing a solution comprising 0.05 M HCl solution with 5 ppm elemental copper; and (ii) reconstituting the 64 Cu eluate in the 5 ppm copper in 0.05 M HCl solution.
  • FIG.4A presents a schematic of an iteration of the process to prepare a 5 ppm elemental copper in 0.05 M HCl solution.
  • the strip solution may optionally be tested using an in-process copper “spot” test to determine the level of elemental copper in the strip solution. The process may proceed to purification if the result is less than about 20 ppm.
  • a second test may be performed at a determination level of 60 ppm. The process may proceed to purification if the result is less than 60 ppm, and the strip solution may be abandoned if the result is greater than 60 ppm. This process control point ensures that the level of elemental copper remains below the specification of not more than 75 ppm.
  • the 64 Cu eluate is reconstituted with about 5 ppm elemental copper in 0.05 M HCl solution. If the in- process spot test result is greater than about 20 ppm but less than about 60 ppm, the 64 Cu eluate may be reconstituted with 0.05 M HCl solution (no additional copper).
  • FIG.4B presents a schematic of an iteration of the process to reconstitute the 64 Cu eluate in a 5 ppm copper in 0.05 M HCl solution.
  • the strip solution may optionally be tested using an in-process copper “spot” test to determine whether a lower level of elemental copper is present in the strip solution.
  • the presence of elemental copper is tested to determine if it is greater than about 5 ppm but less than about 20 ppm, about 25 ppm, about 30 ppm, about 35 ppm, about 40 ppm, about 50 ppm, or about 55 ppm.
  • the test then identifies the concentration limit of elemental copper that is desired for a particular radiopharmaceutical. If the batch exceeds a particular concentration of elemental copper, the batch is discarded.
  • the present disclosure further includes a cyclotron configured to produce high activity amounts of 64 Cu.
  • the cyclotron utilized in the present invention was uniquely designed to be configured to operate at a lower energy and/or a higher amperage.
  • the cyclotron disclosed herein may operate at a higher current up to 1200 ⁇ A and at lower MeV energies below 15 MeV, while previous cyclotrons usually only operated up to 800 ⁇ A at an energy of 15 MeV to 30 MeV.
  • the cyclotron may produce a proton beam with current of at least 800 ⁇ A, at least 850 ⁇ , at least 900 ⁇ , at least 950 ⁇ , at least 1000 ⁇ A, at least 1100 ⁇ A, or at least 1200 ⁇ A.
  • the beam may be split between multiple targets.
  • the cyclotron disclosed herein may be configured to operate at energy levels lower than 15 MeV, while previous cyclotrons usually only operated at energy levels of 15 MeV to 30 MeV.
  • the cyclotron may be configured to generate a proton beam with an energy of up to 30 MeV, 15 MeV, 14 MeV, 13 MeV, 12 MeV, 11 MeV, or 10 MeV.
  • a beam energy of 13 to 30 MeV may be important for the production of 64 Cu.
  • 56 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 an example, when bombarding the target with 13 MeV energy, the attrition of power decreases as it passes through the 64 Ni to the key energy of 11 MEV, which may be the optimal energy to turn 64 Ni into 64 Cu.
  • the cyclotron configured to produce both lower energy and higher current used with the cyclotron target and processes as described herein then allows for the production of higher activity 64 Cu that was not achievable with the energy and current specifications of previously used cyclotrons.
  • the present disclosure also includes a cyclotron target that may be used with the cyclotron for generating radionuclides.
  • the target may include a target body and a beam plate.
  • the target body has a top surface, a bottom surface, and a side surface around the sides of the target body between the top surface and the bottom surface.
  • the target body may have a ledge extending from the bottom surface.
  • the beam plate has a top surface and a bottom surface.
  • the target body and beam plate are connected using a plurality of screws and O-rings.
  • the top surface of the target body may interface with the bottom surface of the beam plate when connected.
  • the beam plate and the target body may have a length of about 50 mm to about 200 mm, about 50 mm to about 75 mm, about 75 mm to about 100 mm, about 100 mm to about 125 mm, about 125 mm to about 150 mm, about 150 mm to about 175 mm, or about 175 mm to about 200 mm.
  • the target may have a width of about 50 mm to about 100 mm, about 50 mm to about 60 mm, about 60 mm to about 70 mm, about 70 mm to about 80 mm, about 80 mm to about 90 mm, or about 90 mm to about 100 mm.
  • the ledge of the target body may extend 3 mm to 10 mm from the target body.
  • the target body may have a length and width that is 6 mm to 200 mm larger than the beam plate.
  • the target may have a height of about 15 mm to about 45 mm, about 15 mm to 25 mm, about 25 mm to about 30 mm, about 30 mm to about 35 mm, or about 35 mm to 45 mm.
  • the beam plate may have a height/thickness of about 3 mm to about 10 mm, about 3 mm to about 5 mm, about 4 mm to about 6 mm, about 5 mm to about 7 mm, about 6 mm to about 8 mm, about 7 mm to about 9 mm, about 8 mm to about 10 mm, about 4 mm to about 4.5 mm, about 4.5 mm to about 5 mm, about 5 mm to about 5.5 mm, about 5.5 mm to about 6 mm, 57 100563663.1 Atty. Docket No.
  • the beam plate may have a thickness of about 6 mm.
  • the target may be plated with materials to be used in generating a desired radionuclide, such as 64 Cu or 68 Ge.
  • the beam plate may further include any material that can be electroplated.
  • the beam plate may include a pocket cut into the top surface of the beam plate. The pocket may be configured to contain a non-solid material that cannot be electroplated.
  • the pocket may be configured to contain nickel germanium.
  • the beam plate does not need to include a pocket.
  • the beam plate may include enriched nickel with electroplated copper.
  • the target body may further include an inlet for receiving a flow of water connected to an inlet of the beam plate and an outlet for receiving the flow of water from an outlet of the beam plate, such that water flows through the inlet of the target body, into the inlet of the beam plate, through a plurality of channels/cooling fins in the beam plate, out the outlet of the beam plate, and out the outlet of the target body.
  • the beam plate may have 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 channels/cooling fins.
  • the beam plate may have 5 to 10, 10 to 15, 15 to 20, 20 to 25, 25 to 30, 30 to 40, or 40 to 50 channels/cooling fins.
  • Each channel/cooling fin may have a width of about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.8 mm, about 0.9 mm, or about 1 mm.
  • Each channel/cooling fin may have a height ranging from about 3.5 mm to about 5.5 mm, about 3.5 mm to about 4 mm, about 4 mm to about 4.5 mm, about 4.5 mm to about 5 mm, or about 5 mm to about 5.5 mm.
  • the channels/cooling fins may have the same height, different height, or combinations thereof.
  • the water flow area within each of the channels/cooling fins may range from about 2 mm 2 to about 2.5 mm 2 , about 2.5 mm 2 to about 3 mm 2 , or about 3 mm 2 to about 3.5 mm 2 .
  • the channels/cooling fins may be spread across the beam plate and generally covers at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% of the length and/or width of the beam plate.
  • the beam plate may have a higher water flow area (i.e. more heat removed from the beam plate) as compared to prior targets with only 2-3 channels or water flow areas.
  • the water flow area within the target and cooling fins may range from 40 mm 2 to 45 mm 2 , 45 mm 2 to 50 mm 2 , 50 mm 2 to 55 mm 2 , 55 mm 2 to 60 mm 2 , 60 mm 2 to 65 mm 2 , 65 mm 2 to 70 mm 2 , 70 mm 2 to 75 mm 2 , 75 mm 2 to 80 mm 2 , 80 mm 2 to 85 mm 2 , or 85 mm 2 to 90 mm 2 .
  • the water flow area through 25 channels/cooling fins is about 77 mm 2 to 78 mm 2 .
  • the water flow rate within the target and cooling fins may range from 40 L/min to 90 L/min, 50 L/min to 90 L/min, 55 L/min to 90 L/min, 40 L/min to 50 L/min, 50 L/min to 55 L/min, 55 L/min to 60 L/min, 60 L/min to 65 L/min, 65 L/min to 70 L/min, 70 L/min to 75 L/min, or 75 L/min to 80 L/min, 80 L/min to 85 L/min, or 85 L/min to 90 L/min.
  • the channels/cooling fins may be rectangular in shape, cylindrical in shape, oval in shape, or have one rounded edge or end.
  • having a radius along a top edge of each of the channels/cooling fins improves the water cooling efficiency by up to 5%, up to 7%, or up to 10%, as compared to channels/cooling fins with a squared edge.
  • the inlet and outlet of the beam plate may include cutout portions to widen the inlet to match the width of the area covered by the plurality of channels/cooling fins. This may reduce the turbulence of the water from the inlet entering the channels/cooling fins.
  • the target may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 screws. The screws may be positioned around the perimeter of the beam plate and extend through the top surface of the target body to secure the beam plate to the target body.
  • the target body may further include one or more holes on the side surface. In some embodiments, there may be a hole at each location where a screw is within the target body. The hole may be perpendicular to the length of each screw. The holes may help to pull air out of the target and improve the pump down of the target.
  • the target may include 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 O-rings.
  • the target may include an outer O-ring, an inner O-ring, an inlet O-ring, and an outlet O-ring.
  • the outer O-ring may be configured to surround the outer surface of the target body. For example, the circumference of the outer O-ring may be 59 100563663.1 Atty. Docket No.
  • the outer O-ring may rest on the ledge extending from the bottom surface of the target body.
  • the inner O-ring may be configured to be within the interface of the target body and the beam plate.
  • the target body may have an inset configured to hold the inner O-ring.
  • the inset may be around the perimeter of the top surface of the target body.
  • the inlet O-ring may be positioned within the inlet of the target body and the outlet O-ring may be positioned within the outlet of the target body.
  • the beam plate may include one or more notches that are configured to receive one or more protrusions of the target base.
  • the protrusions may have a triangular, pointed shape.
  • the notch may be a 90 degree (i.e., 90°) angle.
  • protrusions and corresponding notches may be located where there is high point pressure. The shape and location of the protrusion and corresponding notch may help to minimize water to vacuum leak when thermal shock appears.
  • the notch may cut into an O-ring to minimize steam pressure and leaking.
  • the beam plate may be made of copper and may be plated with further materials.
  • the beam plate may be made of oxygen-free Cu Alloy 101.
  • the target base may be made of aluminum.
  • the target body may be made of Alu 6061-T6.
  • the screws may be made of stainless steel.
  • the screws may be made of SS 18-8.
  • the O-rings may be any O-ring known in the art, including but not limited to Viton® 2-152 durometer 75A, Buna-N AS5668A Dash No 2-212, Markez® Durometer 75A (2-152) W35760, any equivalent FFKM O-ring, or any suitable fluoroelastomer O-ring.
  • the target base may include one or more openings in the lower surface for reducing the weight of the target.
  • the target base may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 openings to reduce the weight of the target.
  • the openings may have the same diameter, a different diameter, or combinations thereof.
  • the target may have a weight ranging from 400 g to 600 g, 400 g to 450 g, 450 g to 500 g, 500 g to 550 g, or 550 g to 600 g.
  • the target may have a weight that allows it to be transported in a transport tube in a hot cell. For example, the 60 100563663.1 Atty. Docket No.
  • C-US-009 WO1 total target weight, including the O-rings, may be about 502 g for a copper target and about 496 g for a germanium target.
  • the plating material may have a weight ranging from 450 mg to 650 mg, 450 mg to 475 mg, 475 mg to 500 mg, 500 mg to 525 mg, 525 mg to 550 mg, 550 mg to 575 mg, 575 mg to 600 mg, 600 mg to 625 mg, or 625 mg to 650 mg.
  • the beam plate may have a plated surface area of 2000 mm 2 to 3000 mm 2 , 2000 mm 2 to 2100 mm 2 , 2100 mm 2 to 2200 mm 2 , 2200 mm 2 to 2300 mm 2 , 2300 mm 2 to 2400 mm 2 , 2400 mm 2 to 2500 mm 2 , 2500 mm 2 to 2600 mm 2 , 2600 mm 2 to 2700 mm 2 , 2700 mm 2 to 2800 mm 2 , 2800 mm 2 to 2900 mm 2 , or 2900 mm 2 to 3000 mm 2 .
  • Design requirements for cGMP Hot Cells for recovering and purification of a radioactive Isotope for recovering and purification of a radioactive Isotope.
  • the Hot Cells Interior may be designed as a Grade C Environment, to eliminate possible contamination inside the Cells. (The official environmental classification for validation and commercial operation may remain Controlled Unclassified).
  • the Hot Cells may be adjoined by guillotine doors with each other, completely furnished, shielded enclosures. Lead shielding may be for up to 107 Ci of 64 Cu. [0176] To safely process up to 107 Ci of 64 Cu several distinct design considerations were needed. For safe and effective transport of the irradiated target, a target transport tube equipped to transfer the larger targets had to be built. The target strip cell was designed to hold the new target. The final product volumes will increase with activity, so a PLC controlled dispenser was programmed to accurately deliver solution volumes to meet product concentration requirements.
  • the hot cell may include chamber coating for acid resistance (e.g. SR65 ethylenechlorotrifluoroethylene (ECTFE)), a shielding requirement equivalent to shield up to 107 Ci of 64 Cu, two tele-manipulators per hot cell, a pneumatically operated target send / receive station, shielded waste chambers, a guillotine door connecting hot cells, the ability to operate under negative pressure, and an ionization chamber (dose calibrator) for sample measurements.
  • ECTFE ethylenechlorotrifluoroethylene
  • composition 1 the present disclosure provides a composition comprising from about 20 Ci to about 110 Ci of isolated copper-64 ( 64 Cu) and having a specific activity up to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Composition 2 the present disclosure provides a composition comprising from about 20 Ci to about 110 Ci of 64 Cu at the end of bombardment (EOB) of a single cyclotron run.
  • Composition 3 the present disclosure provides a composition comprising from about 2 Ci to about 5 Ci of 64 Cu at EOB of a single cyclotron run of about 2 h or about 4 h.
  • Composition 4 the present disclosure provides a composition comprising from about 5 Ci to about 9 Ci of 64 Cu at EOB of a single cyclotron run of about 6 h.
  • Composition 5 the present disclosure provides a composition comprising up to about 15 Ci of 64 Cu at EOB of a single cyclotron run of about 12 h.
  • Composition 6 the present disclosure provides a composition, as provided in any one of Compositions 1 to 5, wherein the composition has a specific activity from about 40 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Composition 7 the present disclosure provides a composition, as provided in any one of Compositions 1 to 6, wherein the composition has a specific activity from about 40 mCi 64 Cu/ ⁇ g Cu to about 2300 mCi 64 Cu/ ⁇ g Cu.
  • Composition 8 the present disclosure provides a composition, as provided in any one of Compositions 3 to 7, wherein the single cyclotron run comprises bombarding a nickel-64 target with a beam of protons having an energy of about 12 MeV to about 14 MeV. 62 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 [0187]
  • Composition 9 the present disclosure provides a composition, as provided in any one of Compositions 1 to 8, wherein the composition has a total content of trace metals of less than about 5 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.
  • Composition 10 the present disclosure provides a composition, as provided in any one of Compositions 1 to 9, wherein the composition comprises a solution of hydrochloric acid (HCl).
  • Composition 11 the present disclosure provides a composition, as provided in Composition 10, wherein the solution comprises about 0.001 M to about 3 M HCl.
  • Composition 12 the present disclosure provides a composition, as provided in Compositions 10 or 11, wherein the solution comprises about 2 M HCl.
  • Composition 13 the present disclosure provides a composition, as provided in any one of Compositions 10 to 12, wherein the solution comprises about 0.05 M HCl.
  • Composition 14 the present disclosure provides a composition, as provided in any one of Compositions 10 to 13, wherein the 64 Cu exists as 64 CuCl2.
  • Composition 15 the present disclosure provides a composition, as provided in any one of Compositions 1 to 14, wherein the composition further comprises a chelating agent or a bifunctional chelating agent in which the 64 Cu is coordinated therein.
  • Composition 16 the present disclosure provides a composition, as provided in Composition 15, wherein the chelating agent or the bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.
  • Composition 17 the present disclosure provides a composition, as provided in Compositions 15 or 16, wherein the bifunctional chelating agent is DOTA. 63 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1
  • Composition 18 the present disclosure provides a solution comprising (i) about 2 Ci to about 15 Ci of 64 Cu that has a specific activity up to about 3800 mCi 64 Cu/ ⁇ g Cu and (ii) HCl.
  • Composition 19 the present disclosure provides a composition, as provided in Composition 18, wherein the specific activity of the solution is from about 40 mCi 64 Cu/ ⁇ g Cu to about 2300 mCi 64 Cu/ ⁇ g Cu.
  • Composition 20 the present disclosure provides a composition, as provided in Compositions 18 or 19, wherein the HCl has a concentration from about 0.001 M to about 3 M.
  • Composition 21 the present disclosure provides a composition, as provided in any one of Compositions 18 to 20, wherein the HCl has a concentration of about 0.5 M.
  • Composition 22 the present disclosure provides a composition, as provided in any one of Compositions 18 to 21, wherein the 64 Cu exists as 64 CuCl2.
  • Composition 23 the present disclosure provides a composition, as provided in any one of Compositions 18 to 22, wherein the solution has a total content of trace metals of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.
  • Composition 24 the present disclosure provides a composition, as provided in any one of Compositions 18 to 23, wherein the solution further comprises a chelating agent or a bifunctional chelating agent in which the 64 Cu is coordinated therein.
  • Composition 25 the present disclosure provides a composition, as provided in Composition 25, wherein the chelating agent or the bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.
  • Composition 26 the present disclosure provides a composition, as provided in Compositions 24 or 25, wherein the bifunctional chelating agent is DOTA. 64 100563663.1 Atty. Docket No.
  • Process 1 provides a process for preparing copper-64 ( 64 Cu) from nickel-64 ( 64 Ni), the process comprising (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of hydrochloric acid (HCl) having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni and 64 Cu; and (c) purifying the 64 Cu from the strip solution by ion exchange chromatography comprising: (i) passing the strip solution through a column comprising an ion exchange resin such that 64 Cu binds to the ion exchange resin and 64 Ni passes through the column as a flow-through; (ii) rinsing the column with a volume of HCl having a molarity of about 3 M to about 6 M;
  • Process 2 the present disclosure provides a process, as provided in Process 1, wherein the cyclotron target comprises about 50 mg of 64 Ni plated in an area of about 4.0 cm 2 .
  • Process 3 the present disclosure provides a process, as provided in Processes 1 or 2, wherein the proton beam has an energy of about 10 MeV to about 14 MeV and a current of about 100 ⁇ A to about 250 ⁇ A.
  • Process 4 the present disclosure provides a process, as provided in any one of Processes 1 to 3, wherein the proton beam has an energy of about 12 MeV and a current up to about 225 ⁇ A.
  • Process 5 the present disclosure provides a process, as provided in any one of Processes 1 to 4, wherein the bombarding proceeds for about 1 h to about 6 h.
  • Process 6 the present disclosure provides a process, as provided in any one of Processes 1 to 5, wherein after the bombarding, the bombarded target comprises from about 2 Ci to about 12 Ci of 64 Cu at the end of bombardment (EOB).
  • EOB end of bombardment
  • Process 7 the present disclosure provides a process, as provided in Process 6, wherein after about 2 h to about 4 h of bombarding, the bombarded target comprises from about 2 Ci to about 5 Ci of 64 Cu at EOB. 65 100563663.1 Atty. Docket No.
  • Process 8 the present disclosure provides a process, as provided in Process 6, wherein after about 6 h of bombarding, the bombarded target comprises from about 5 Ci to about 9 Ci of 64 Cu at EOB.
  • Process 9 the present disclosure provides a process, as provided in any one of Processes 1 to 8, wherein the stripping of the bombarded target is conducted at a temperature of about 65 ⁇ C to about 100 ⁇ C.
  • Process 10 the present disclosure provides a process, as provided in any one of Processes 1 to 9, wherein the stripping comprises contacting the bombarded target three times with an aliquot of 9 M HCl for about 3-5 minutes each time, and collecting the aliquots as the strip solution.
  • Process 11 the present disclosure provides a process, as provided in any one of Processes 1 to 10, wherein the bombarded target is rinsed with an additional aliquot of 9 M HCl, which is then added to the strip solution.
  • Process 12 the present disclosure provides a process, as provided in any one of Processes 1 to 11, wherein the ion exchange resin is a strong anion exchange resin comprising trimethylbenzyl ammonium chloride groups.
  • Process 13 the present disclosure provides a process, as provided in any one of Processes 1 to 12, wherein the flow-through from passing the strip solution through the column is collected as a 64 Ni recovery fraction.
  • Process 14 the present disclosure provides a process, as provided in any one of Processes 1 to 13, wherein after passing the strip solution through the column, a further volume of 9 M HCl is added to the column and its flow-through is combined with the 64 Ni recovery fraction.
  • Process 15 the present disclosure provides a process, as provided in Process 14, wherein an average of about 82% of the target 64 Ni is recovered in the 64 Ni recovery fraction.
  • Process 16 the present disclosure provides a process, as provided in any one of Processes 1 to 15, wherein the rinsing comprises adding 4 M HCl to the column to elute cobalt, which is collected as a waste fraction. 66 100563663.1 Atty. Docket No.
  • Process 17 the present disclosure provides a process, as provided in any one of Processes 1 to 16, wherein the 64 Cu is eluted form the column with 2 M HCl.
  • Process 18 the present disclosure provides a process, as provided in any one of Processes 1 to 17, wherein an average of about 80% of the 64 Cu present in the strip solution is recovered in the eluate comprising 64 Cu.
  • Process 19 the present disclosure provides a process, as provided in any one of Processes 1 to 18, wherein the eluate comprising 64 Cu is evaporated to dryness and reconstituted in 0.05 M HCl, thereby forming a final product comprising 64 Cu.
  • Process 20 the present disclosure provides a process, as provided in Process 19, wherein the final product comprising 64 Cu comprises from about 2 Ci to about 12 Ci of 64 Cu.
  • Process 21 the present disclosure provides a process, as provided in Processes 19 or 20, wherein the final product comprising 64 Cu has a specific activity up to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Process 22 the present disclosure provides a process, as provided in any one of Processes 19 to 21, wherein the final product comprising 64 Cu has a specific activity from about 40 mCi 64 Cu/ ⁇ g Cu to about 2300 mCi 64 Cu/ ⁇ g Cu.
  • Process 23 the present disclosure provides a process, as provided in any one of Processes 19 to 22, wherein the final product comprising 64 Cu has a total content of trace metals of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, gallium, germanium, zinc, and combinations thereof.
  • Process 24 provides an additional process for preparing copper-64 (64Cu) from nickel-64 (64Ni), in which the 64 Cu is purified by a combination of extraction chromatography and ion exchange chromatography.
  • the process comprises (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of HCl having a molarity of about 6 M to about 12.1 M to form a 67 100563663.1 Atty. Docket No.
  • C-US-009 WO1 strip solution comprising 64 Ni, 64 Cu, 61 Co, and one or more trace metals; and (c) purifying the 64 Cu from the strip solution by chromatography, wherein the chromatography comprises (i) passing the strip solution through a first column comprising an extraction resin connected in series to a second column comprising an ion exchange resin, such that the one or more trace metals binds to the extraction resin in the first column, 64 Cu and 61 Co bind to the ion exchange resin in the second column, and 64 Ni passes through both columns as a first flow-through fraction.
  • the process further comprises (ii) rinsing the first and second columns with a volume of HCl having a molarity of about 6 M to about 12.1 M to remove residual 64 Ni as a second flow-through fraction; (iii) rinsing the second column with a volume of HCl having a molarity of about 3 M to about 6 M to elute 61 Co as a first waste fraction; (iv) rinsing the second column with a volume of NaCl having a molarity of about 3 M to 6 M in HCl having a molarity of about 0.01 M to about 3 M to elute residual 61 Co as a second waste fraction or rinsing the second column with an additional volume of HCl having a molarity of about 3 M to about 6 M to elute 61 Co as a second waste fraction; and (v) adding a volume of HCl having a molarity of about 0.01 M to about 3 M to the second column to
  • Process 25 the present disclosure provides a process, as provided in Process 24, wherein the cyclotron target at (a) comprises about 750 mg of 64 Ni plated in an area of about 23.0 cm 2 .
  • Process 26 the present disclosure provides a process, as provided in Processes 24 or 25, wherein the proton beam at (a) has an energy of about 10 MeV to about 15 MeV and a current of about 350 ⁇ A to about 408 ⁇ A.
  • Process 27 the present disclosure provides a process, as provided in any one of Processes 24 to 26, wherein the proton beam at (a) has an energy of about 13 MeV and a current of about 350 ⁇ A to about 408 ⁇ A.
  • Process 28 the present disclosure provides a process, as provided in any one of Processes 24 to 27, wherein the bombardment (a) proceeds for about 12 h to about 24 h, and the bombarded target comprises from about 46 Ci to about 82 Ci of 64 Cu at the end of bombardment (EOB). 68 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 [0233]
  • Process 29 the present disclosure provides a process, as provided in Processes 28, wherein after about 16 h to about 20 h of bombarding at (a), the bombarded target comprises from about 56 Ci to about 75 Ci of 64 Cu at EOB.
  • Process 30 the present disclosure provides a process, as provided in Processes 28, wherein after about 19 h of bombarding at (a), the bombarded target comprises from about 62 Ci to about 73 Ci of 64 Cu at EOB.
  • Process 31 the present disclosure provides a process, as provided in any one of Processes 24 to 30, wherein the stripping at (b) comprises contacting the bombarded target with 9 M HCl, and the stripping at (b) is conducted at a temperature of about 65 ⁇ C to about 100 ⁇ C.
  • Process 32 the present disclosure provides a process, as provided in any one of Processes 24 to 31, wherein the extraction resin in the first column at (c)(i) comprises tributylphosphate as a functional group, and the ion exchange resin in the second column at (c)(i) comprises a tertiary amine as a functional group.
  • Process 33 the present disclosure provides a process, as provided in any one of Processes 24 to 32, wherein the rinsing at (c)(ii) comprises 9 M HCl.
  • Process 34 the present disclosure provides a process, as provided in any one of Processes 24 to 33, wherein the first and second flow-through fractions are combined as a 64 Ni recovery fraction.
  • Process 35 the present disclosure provides a process, as provided in Process 34, wherein an average of about 98% of the target 64 Ni is recovered in the 64 Ni recovery fraction.
  • Process 36 the present disclosure provides a process, as provided in any one of Processes 24 to 35, wherein the rinsing at (c)(iii) comprises 4 M HCl, and the rising at (c)(iv) comprises 5 M NaCl in 0.05 M HCl or additional 4 M HCl.
  • Process 37 the present disclosure provides a process, as provided in any one of Processes 24 to 36, wherein the 64 Cu is eluted at (c)(v) with 0.05 M HCl.
  • Process 38 the present disclosure provides a process, as provided in any one of Processes 24 to 37, wherein an average of about 89% of the 64 Cu present in the strip solution is recovered in the product fraction comprising 64 Cu.
  • Process 39 the present disclosure provides a process, as provided in any one of Processes 24 to 38, wherein the product fraction comprising 64 Cu comprises from about 2 Ci to about 15 Ci of 64 Cu and has a specific activity up to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Process 40 the present disclosure provides a process, as provided in any one of Processes 24 to 39, wherein the product fraction comprising 64 Cu has a total content of trace metals of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.
  • Process 41 provides a process for preparing 64 Cu from 64 Ni, the process comprising (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of hydrochloric acid (HCl) having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and one or more other metals; and (c) purifying the 64 Cu from the strip solution by (i) passing the strip solution through a column comprising an ion exchange resin such that the one or more other metals binds to the ion exchange resin in the column, 64 Cu and 61 Co bind to the ion exchange resin in the column and 64 Ni passes through the column as a first flow- through fraction; (ii) rinsing the column with a volume of HCl having a molarity of about 6 M to about 12.1 M to
  • Process 42 provides a process for preparing 64 Cu from 64 Ni, the process comprising (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of hydrochloric acid (HCl) having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and one or more other metals; and (c) purifying the 64 Cu from the strip solution by (i) passing the strip solution through a column comprising an ion exchange resin such that 64 Cu binds to the ion exchange resin and 64 Ni passes through the column as a first flow-through fraction; (ii) rinsing the column with a volume of HCl having a molarity
  • Process 43 the present disclosure provides a process, as provided in any one of Processes 1 to 42, wherein the plated material weight is from about 40 mg to about 800 mg.
  • Process 44 the present disclosure provides a process, as provided in any one of Processes 1 to 43, wherein the plated material weight is from about 550 mg to about 605 mg.
  • Process 45 the present disclosure provides a process, as provided in any one of Processes 1 to 44, wherein the plated surface area (also referred to as the plating area) is from about 3.0 cm 2 to about 25 cm 2 .
  • Process 46 the present disclosure provides a process, as provided in any one of Processes 1 to 45, wherein the plated surface area (also referred to as the plating area) is from about 21 cm 2 to about 24 cm 2 .
  • Process 47 the present disclosure provides a process, as provided in Processes 1 to 46, wherein the proton beam has an energy of about 10 MeV to about 14 MeV and a current of about 30 ⁇ A to about 1200 ⁇ A.
  • Process 48 the present disclosure provides a process, as provided in any one of Processes 1 to 47, wherein the proton beam has an energy of about 13 MeV and a current of about 408 ⁇ A.
  • Process 49 the present disclosure provides a process, as provided in any one of Processes 1 to 48, wherein the target is cooled using water flow through the target. The water flows through a series of cooling fins along the length of the target. The target includes 5 to 50 cooling fins.
  • Process 50 the present disclosure provides a process, as provided in any one of Processes 1 to 49, wherein the water flow surface area within the target and cooling fins ranges from 40 mm 2 to 90 mm 2 .
  • Process 51 the present disclosure provides a process, as provided in any one of Processes 1 to 50, wherein the water flow rate within the target and cooling fins ranges from 40 L/min to 90 L/min.
  • Process 52 the present disclosure provides a process, as provided in any one of Processes 1 to 51, wherein the water flow rate within the target and cooling fins ranges from 50 L/min to 90 L/min.
  • Process 53 the present disclosure provides a process, as provided in any one of Processes 1 to 52, wherein the water flow rate within the target and cooling fins ranges from 55 L/min to 90 L/min.
  • Process 54 the present disclosure provides a process, as provided in any one of Processes 1 to 53, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and has a specific activity up to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Process 55 the present disclosure provides a process, as provided in any one of Processes 1 to 54, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and has a specific activity from about 50 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Process 56 the present disclosure provides a process, as provided in any one of Processes 1 to 55, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and has a specific activity from about 100 mCi 64 Cu/ ⁇ g Cu to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Process 57 the present disclosure provides a process, as provided in any one of Processes 1 to 56, wherein the product fraction 72 100563663.1 Atty. Docket No.
  • C-US-009 WO1 comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and has a specific activity from about 50 mCi 64 Cu/ ⁇ g Cu to about 6000 mCi 64 Cu/ ⁇ g Cu.
  • Process 58 the present disclosure provides a process, as provided in any one of Processes 1 to 57, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and has a specific activity from about 100 mCi 64 Cu/ ⁇ g Cu to about 6000 mCi 64 Cu/ ⁇ g Cu.
  • Process 59 the present disclosure provides a process, as provided in any one of Processes 1 to 58, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and less than 10 ppm of 67 Cu, less than 9 ppm of 67 Cu, less than 8 ppm of 67 Cu, less than 7 ppm of 67 Cu, less than 6 ppm of 67 Cu, or less than 5 ppm of 67 Cu.
  • Process 60 provides a process, as provided in any one of Processes 1 to 59, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and less than 4 ppm of 67 Cu, less than 3 ppm of 67 Cu, less than 2 ppm of 67 Cu, less than 1 ppm of 67 Cu, less than 0.1 ppm of 67 Cu, or less than 0.05 ppm of 67 Cu.
  • Process 61 provides a process, as provided in any one of Processes 1 to 60, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and less than 10 ppm of 68 Zn, less than 9 ppm of 68 Zn, less than 8 ppm of 68 Zn, less than 7 ppm of 68 Zn, less than 6 ppm of 68 Zn, or less than 5 ppm of 68 Zn.
  • Process 62 provides a process, as provided in any one of Processes 1 to 61, wherein the product fraction comprising 64 Cu comprises from about 15 Ci to about 110 Ci of 64 Cu and less than 4 ppm of 68 Zn, less than 3 ppm of 68 Zn, less than 2 ppm of 68 Zn, less than 1 ppm of 68 Zn, less than 0.1 ppm of 68 Zn, or less than 0.05 ppm of 68 Zn.
  • Process 63 provides a process, as provided in any one of Processes 1 to 62, wherein the product fraction comprising from about 15 Ci to about 110 Ci of 64 Cu and 0 ppm 68 Zn (i.e., an absence of 68 zinc). 73 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 DEFINITIONS [0268]
  • the features, structures, steps, or characteristics disclosed herein in connection with one embodiment may be combined in any suitable manner in one or more alternative embodiments.
  • carrier refers to an inactive material deliberately added to a specified radioactive substance to ensure that the radioactivity will behave normally in all subsequent chemical and physical processes.
  • non-carrier added refers to a preparation of a radioactive isotope which is 'free' from stable isotopes of the element in question.
  • a glass Econo- column (0.7 cm x 20 cm) was dry-packed with 4.5 g of AG 1-X8 resin (16 cm bed height, 6 mL bed volume). The resin was pre-treated by washing the column with 30 mL of Chelex-treated H2O followed by 30 mL of 6 M HCl. This rinse cycle was repeated once more so that the final wash was with 6 M HCl. The columns were gravity drained and each wash was considered complete once droplet formation ceased. [0278] The column was loaded with 10 mL of the metal solution (50 mg Ni, 250 ⁇ g each added metal) and the flow through was collected as 2 x 5 mL fractions (load fraction).
  • the column was eluted with the following: 5 x 2 mL aliquots of 6 M HCl (6 M fraction), 5 x 2 mL aliquots of 4 M HCl (4 M fraction), 5 x 2 mL aliquots of 2 M HCl (2 M fraction), and 1 x 5 mL aliquot of 0.5 M HCl (0.5 M fraction).
  • Each eluate and an aliquot of the initial unpurified mixture were analyzed by Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES).
  • Table 1 presents the amount of metal present in each fraction as a percentage of what was present in the initial unpurified mixture.
  • Example 2 Varying Molarity of Starting Acid
  • a solution containing 5.0 mg/mL Ni and 25 ⁇ g/mL each of Co, Cu, Fe, Zn, Hg and Pb in 9 M HCl was prepared.
  • a column comprising 4.5 g of AG 1-X8 resin was prepared described above in Example 1. The column resin was pre-treated with 30 mL of Chelex-treated H2O followed by 30 mL of 9 M HCl. This rinse cycle was repeated once more so that the final wash was with 9 M HCl.
  • the prepped column was loaded with 10 mL of the Ni solution (50 mg Ni, 250 ⁇ g each added metal) and collected as 2 x 5 mL fractions.
  • the column then was eluted, and fractions collected with the following: 5 x 2 mL fractions of 9 M HCl, 5 x 2 mL fractions of 4 M HCl, 5 x 2 mL fractions of 2 M HCl, and 1 x 5 mL of 0.5 M HCl.
  • Samples of the eluates and the initial unpurified mixture were analyzed via ICP-OES. These data are presented in Table 2. 76 100563663.1 Atty. Docket No.
  • Example 3 Adjusting a CS-30 Cyclotron to Reduce Proton Beam Energy
  • Copper-64 may be produced by bombarding enriched nickel-64 with low energy protons (e.g., less than 14 MeV). At higher beam energies, the production of 61 Co and stable 63 Cu increases and 64 Cu production decreases, therefore 64 Cu production from 64 Ni via the (p,n) reaction is best performed with 12 MeV protons.
  • CS-30 cyclotrons were not suitable for 64 Cu production because they may accelerate a proton beam up to about 30 MeV. It is generally accepted that a cyclotron cannot attain a beam energy lower than half of its maximum energy.
  • the lowest energy attainable in CS-30 cyclotrons is about 15 MeV.
  • FIG.3 shows the proton energy as a function of the proton beam radius. This plot predicts a target radius of about 27.9 cm to attain a beam energy of about 12 MeV.
  • the location of the target was adjusted in the cyclotron so that the proton beam would strike the target at the smaller radius of about 27.9 cm.
  • Initial beam strikes with CS-30 curved targets showed that the proton beam went too far along one edge of the target, all of the way to the end, with no beam on the majority of the target face, completely missing the opposite edge.
  • Example 4 Target Bombardments of Enriched Nickel-64 [0288]
  • a CS-30 cyclotron adjusted as described above in Example 3 was used to produce 64 Cu.
  • about 50 mg of 64 Ni ( ⁇ 99% isotopically enriched) was electroplated on a CS-30 cyclotron flat target comprising a copper base layer that had been electroplated with gold to a thickness of about 50 ⁇ m.
  • the plated area was about 4.0 cm 2 .
  • the target was bombarded with a beam energy of about 12 MeV, a beam current of 200 ⁇ A or 225 ⁇ A, and bombardment time of 1 to 6 h.
  • the target was bombarded for 1 to 6 h with a beam energy of about 12 MeV and beam current of approximately 200 ⁇ A or 225 ⁇ A.
  • the bombarded target was stripped using three 3.0 mL aliquots of 9 M HCl. During this time, the target stripping cell was heated to 75 oC, and each aliquot was held for 3-5 minutes. After the hold time, the 3-mL aliquot was removed and placed in a holding vessel. The aliquots were collected together as one, approximately 9 mL strip solution.
  • the 64 Cu was isolated and purified by anion exchange chromatography essentially as described above in Example 2.
  • the column resin was pre- treated by washing twice with Chelex-treated 18.2 M ⁇ .cm resistivity water followed by 9 M HCl.
  • the 9-mL strip solution was loaded onto a pre-treated ion-exchange column along with an additional 1 mL of 9 M HCl that was used to rinse the vessel holding the strip solution.
  • the 10-mL load volume was eluted from the column by gravity at ⁇ 1 mL per minute as the load fraction. Gravity filtration was used for all the solutions that passed through the column.
  • the column was then rinsed with another 10 mL of 9 M HCl and the eluate was combined with the load fraction.
  • the combined fractions (approximately 20 mL) comprised the 64 Ni recovery fraction. After the 64 Ni recovery fraction was collected from the column, 10 mL of 4 M HCl was added to the column. 79 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1
  • the eluate comprising cobalt was collected separately as a waste fraction.
  • the yield of 64 Cu at EOB for 15 runs ranged from 674 mCi (1 h bombardment at 200 ⁇ A) to 8,706 mCi (6 h bombardment at 200 ⁇ A).
  • the Cu content was determined via ICP-OES. Further analysis revealed no statistically significant difference between the dose calibrator and the HPGe detector. The dose calibrator method was preferred because it was more straightforward to use during manufacturing.
  • the average recovery of 64 Ni (in the 64 Ni recovery fraction) from the 15 processed targets was about 82%.
  • Table 6 presents the specific activity of the 64 Cu product in the 0.05 M HCl solution. 81 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 Table 6. Specific Activity of 64 Cu in 0.05 M HCl Solution Batch 1 Batch Batch 3 0 2 p . p g Chromatography [0295] A trial separation of various metals was performed using a combination of extraction chromatography and ion exchange chromatography to more effectively separate Cu from masses of Ni up to 750 mg, Co, Fe, and other transition metals.
  • a polyethylene (PE) column (0.7 cm x 20 cm) was vacuum-packed using 20 mL of 0.05 M HCl with 2.7 g of TK201 resin (about 5 cm to 6 cm bed height, about 1 mL to 2 mL bed volume).
  • a PE frit was securely placed atop the packed resin bed.
  • the packed PE column, containing TK201 resin was rinsed with 20 mL of 0.05 M HCl under vacuum.
  • the packed PE column was capped and stored at 4.4 ⁇ C.
  • a solution containing 25.0 mg/mL Ni, 20.4 ⁇ g/mL Co, 8.6 ⁇ g/mL Cu, 8.1 ⁇ g/mL Fe, and 10.3 ⁇ g/mL Pb was prepared in 9 M HCl to simulate a bombarded target stripping solution.
  • Table 7 presents the amount of metal present in each fraction as a percentage of the starting amount in the simulated stripping solution mixture. Table 7. Percentages of Various Metals in Each Fraction 5 .* 5 . . [0300] As expected, Ni was present in the load fraction and the 9 M HCl rinse fraction (98.4%). The Cu was measured only in the 0.05 M HCl fraction (86.5%). Co was observed in the load, 9 M HCl, 4 M HCl, and 5 M NaCl fractions, with no co-elution of Cu in the 0.05 M HCl fraction.
  • ICP-OES Inductively Coupled Plasma Optical Emission Spectroscopy
  • Example 7 Analyses of Copper Cu-64 Chloride Compositions [0301] Batches of copper Cu-64 chloride compositions of the present disclosure were prepared as described herein. Six batches were analyzed for quality control, including analysis for elemental impurities, radioactive concentration, 83 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 radionuclidic identity, radionuclidic purity, and specific activity. The data for each batch is provided in Tables 8-13. Table 8.
  • the 30 MeV variable energy cyclotron may be variable in energy down to 13 MeV to maximize production yields for 64 Cu.
  • a variable energy 30 MeV cyclotron may be tuned down to about 15 to about 16 MeV.
  • the cyclotron and ion source may also be capable of producing almost about 0.8 mA of current that may be split along two external beam lines (approximately about 375 ⁇ A per beam line) running simultaneously.
  • FIG.4A presents a schematic of an iteration of the process.
  • Example 10 Improved enrichment of Cu-64 [00286] This example demonstrates compositions with improved enrichment of Ni-64 and methods of making them. Four experimental proton bombardments were performed in a new cyclotron tested herein on one natural nickel and three enriched Ni- 64 targets (650 mg each). The four 13 MeV proton bombardments successfully produced Cu-64, and the enriched Ni- 64 targets produced 2.0, 4.9, and 16.1 Ci of Cu- 64 at end of bombardment at beam currents of 139, 750, and 1500 ⁇ A x hr respectively.
  • the Cu-64 yields for the natural nickel and two of the enriched Ni-64 targets were within 0.2%, 12.7%, and 0.7% of the theoretical values calculated using the thick target yield equation. It was hypothesized that the run that did not match the theoretical yield calculations was not homogenous upon sampling, and therefore, the discrepancy was not due to issues with the new cyclotron during bombardment.
  • the isotopic impurity profiles for the various runs matched the calculated profiles determined based on the nickel isotopes present in the target. As both the Cu-64 yields and impurity profiles matched the theoretical calculations, it was determined that the new cyclotron was operating close to the designated parameters and is ready for production of Cu-64.
  • PET positron-emission tomography
  • Cu-64 product code L064 or 93 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 N164
  • Copper-64 is produced by irradiating enriched Ni-64 targets using CS-30 cyclotrons.
  • the current CS-30 targets used for Cu-64 production consist of a flat copper target body with a 50- ⁇ m protective layer of gold (Au) on the surface, on top of which, 50 mg of enriched Ni- 64 starting material is electroplated over a 4 cm 2 area.
  • a new cyclotron for producing Cu-64 will employ targets that have a larger plating area (23 cm 2 ) that requires larger plated Ni-64 masses of 550 – 750 mg. A larger plating area would allow a larger amount of the target surface to be irradiated. This results in the proton energy being spread over a larger amount of the target; and the heat from the proton beam being spread across more of the target surface.
  • the bombarded targets were then stripped to remove the produced radio isotopes and remaining nickel before analysis using gamma spectroscopy on a high purity germanium (HPGe) detector and inductively coupled plasma optical emission spectroscopy (ICP-OES) to quantify the radioisotopes and metals content. Calculations were performed to estimate the yields from each run and determine if the new cyclotron was operating close to the intended parameters. Additional calculations were carried out to estimate how various cyclotron parameters would impact future Cu-64 yields. Experimental Summaries [00292] Operational summaries of the plating and bombardment work performed during the execution of this protocol are detailed below. For these initial bombardments, a plated target mass of approximately 650 mg per target was selected.
  • Natural Nickel Bombardment – Run 1 Natural Nickel in the form of nickel chloride hexahydrate from Sigma- Aldrich was used to plate the target intended for the first bombardment. Three targets were plated used methods disclosed herein. The plating bath pH was 10.06 and the targets were plated for 2 hours at 500 mA. Target 24Jun24-PB1-2, which was selected for bombardment, had a plated mass of 649 mg. Plated target appearance and adhesion were both acceptable with Pugh Matrix scores of 1. These values correspond to a uniform gray color with no significant defects and no Ni residue on the tape after performing an adhesion test. See Figure 5A for a photo of the plated target.
  • Target bombardment occurred on 11-Jul-24 for 30 minutes at 150 ⁇ A, for a total electric charge of 75 ⁇ A ⁇ hr.
  • End of Bombardment (EOB) was at 0922 on 11-Jul-24.
  • the plated surface of the target during bombardment can be seen in a photo in ( Figure 5B).
  • the target strip cell was set to 92 °C (to reach a target temperature of 60 °C).
  • the target was stripped 3 times each with 12.5 mL of concentrated HCl for 5 minutes. Final strip solution volume was 31 mL.
  • the activity of the consolidated strip solution, by dose calibrator was 10.38 Ci at 1004 on 11-Jul-24.
  • the target was visually inspected to ensure complete removal 95 100563663.1 Atty. Docket No.
  • the vast majority (> 98%) of the target is stripped with the first two acid additions so that the dose calibrator reading taken after the second strip is representative of the majority of the activity produced during the run.
  • the target was visually inspected to ensure complete removal of the plated nickel (Figure 5D).
  • Strip solution samples were submitted for ICP and HPGe analysis.
  • Target bombardment occurred 96 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 on 29-Aug-24 for 2 hours and 11 minutes at 375 ⁇ A, for a total electric charge of 750 ⁇ A ⁇ hr.
  • EOB was at 1021 on 29-Aug-24.
  • the plated surface of the target remained integral during bombardment ( Figure 5E).
  • the target strip was performed identically to the natural nickel target detailed above in this Example. Final strip solution volume was 34.5 mL.
  • a dose calibrator was used to determine the activity of the consolidated strip solutions and was 9.93 Ci at 1110 on 29-Aug-24.
  • Target 30Jul24-PB4-3 was selected for the third Ni-64 target bombardment. This target had a plated mass of 649 mg. Target bombardment occurred on 12-Sep-24 for 4 hours and 35 minutes at 375 ⁇ A, for a total electric charge of 1500 ⁇ A ⁇ hr. EOB was at 1220 on 12-Sep-24. The plated surface of the target remained integral during bombardment (Figure 5F).
  • the target strip was performed identically to the Natural Nickel target detailed above in this Example, except that a 4th strip of 12.5 mL was performed to ensure full removal of the plated nickel. Final strip solution volume was 45.7 mL. A dose calibrator was used to determine the activity of the consolidated strip solutions and was 19.25 Ci at 1321 on 12-Sep-24. After the run, the target was visually inspected to ensure complete removal of the plated nickel (see Figure 5F). Strip solution samples were submitted for ICP and HPGe analysis. Bombardment summary [00298] The table below summarizes the conditions under which bombardments were performed. Table 17 Bombardment summary Target Natural Enriche Enriche Enriche 4- 97 100563663.1 Atty. Docket No.
  • Samples were counted for a length of time so that major peaks of interest for Cu-64 and impurities reached at least 1000 counts for quantitative data at time 0, 1 day, 1 week, 2 weeks, 3 weeks, and 4 weeks post end of bombardment (EOB). This corresponded to count times ranging from 3000 seconds at time 0 to 28800 seconds or longer at 4 weeks post EOB.
  • the isotopes are grouped into three (3) groups based on half-life, displayed in Table 18.
  • Short lived isotopes (t1/2 ⁇ 3.5 hours) are color coded orange, medium-lived isotopes (t1/2 ⁇ 3.5 days and ⁇ 3.5 hours) are color coded blue, and long-lived isotopes (t1/2 ⁇ 5.5 days) are color coded green.
  • the short and medium-lived isotopes may be detected up to 1 week post EOB.
  • Medium-lived isotopes with a half-life greater than 1 day may be detected up to 2-3 weeks post EOB.
  • Long- 98 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 lived isotopes can be detected up to 4 weeks post EOB or even longer.
  • the stopping power was calculated for a natural nickel target using the hydrogen ion with a mass of 1.008 amu and a Nickel-58 mass of 58.69 amu and a density of 8.89550 g/cm 3 ( Figure 6A and following equation) and for an enriched Ni-64 target using the hydrogen ion with a mass of 1.008 amu and a Nickel-64 mass of 63.93 amu and a density of 8.9080 g/cm 3 ( Figure 6B and following equation).
  • the stopping power for the natural nickel target was estimated for ion energies between 0.12 and 20 MeV and the Ni-64 target was estimated between 0.15 and 15 MeV.
  • the total stopping power contributions from both electronic and radiative contributions were summed together to get the total stopping power.
  • Equation 6-8 the equation is kept general by using C8 and P to represent the constant and power of the power fit for the stopping power equation.
  • above equation is separable and can be split into two definite integrals (Equation 6-8) where xeff is the effective thickness of the target (described later). the following equation for the exit energy as a function of the thickness of the plate (following equation). target at a ( Figure 6C), the xeff must be calculated using the following equation. Atty. Docket No.
  • the proton Due to the interactions between the proton and the atoms in the target, the proton slows down before finally reaching an energy of 0 MeV at 30.8 and 32.6 ⁇ m for the natural nickel and Ni-64 targets respectively.
  • a proton with an entrance energy of 13 MeV is estimated to exit the back of the target and embed in the gold target material.
  • the main isotope produced in the bombardment was Cu-60 which is expected to be created by the 60 Ni(p,n) 60 Cu reaction which has a favorable cross section near 13 MeV and is benefited by the higher percentage of Ni-60 present in the natural nickel target (i.e., 26.2%).
  • any experimental error or error inherent to the calculations will increase the percent difference between the calculated and experimentally determined isotopes.
  • the good agreement between the experimental and predicted activities for many of the isotopes indicates that the new cyclotron operated close to the intended parameters for the natural nickel bombardment.
  • Run 2 – Ni-64 Enriched Target 13 MeV, 150 ⁇ A, 1 hr
  • the first enriched Ni-64 target bombarded by the new cyclotron produced roughly 2.0 Ci of Cu-64 using a beam energy of 13 MeV at a beam current of 150 ⁇ A for 1 hr (Table 21 and Figure 7B).
  • the Cu-64 produced during this run was 12.7% higher than the calculated Cu-64 activity using these same conditions. This difference could be due to the conditions of the cyclotron being off compared to the reported values, experimental error in the HPGe measurements, inherent error in the calculation method, or issues caused when the strip solution was spilled (see below). As mentioned previously, many of the isotopes at low activities will be close to or below the limit of quantification of the HPGe which could increase the error in the HPGe measurement. This error in the HPGe measurement likely contributed to the higher percent difference between the experimental and calculated activities for some of these isotopes (i.e., Ni-57) compared to many of the higher activity isotopes.
  • Table 21 Measured and calculated activities of radioactive isotopes produced during the bombardment of an enriched Ni-64 target with a 13 MeV proton beam at 150 ⁇ A for 1 hr (Run 2). Experimentally determined activities were measured on the day of bombardment, 1 day, and 1, 3, and 4 weeks after bombardment and decay corrected to EOB. 107 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 Run 3 – Ni-64 Enriched Target [00329] The quantities of the individual isotopes present in the strip solution for run 3 were assessed using an HPGe at four different measurement timepoints and averaged (Table 22 and Figure 7C).
  • the main isotopic impurity produced during the bombardment of the enriched Ni-64 targets and the only impurity predicted to be produced by proton bombardment of Ni-64 is Co-61 (i.e., 64 Ni(p, ⁇ ) 61 Co).
  • 64 Ni(p, ⁇ ) 61 Co the only impurity predicted to be produced by proton bombardment of Ni-64.
  • their production will be dependent on the concentration of their precursor nickel isotope in the target and can be minimized by using higher purity enriched Ni-64 material.
  • Short lived impurities with half-lives less than 30 min such as Cu-60 and Cu-62, will largely be decayed away within 5 h of EOB. As many of the cobalt isotopes and Ni-57 are longer lived, these will need to be separated from the Cu- 64 using chemical separation methods.
  • Cu-61 has the unique combination of possessing a moderately long half-life of 3.3 hr and being difficult to chemically separate from Cu-64.
  • the 61 Ni(p,n) 61 Cu reaction has a favorable cross section near 13 MeV (i.e., maximum of 508 mb at 10.3 MeV)
  • a high concentration of Ni-61 in the target could lead to a high concentration of Cu-61 in the strip solution such as what was seen in the bombardment of the natural nickel target (Run 1).
  • Some of the low-level isotopic impurities can be explained by proton reactions with impurities present in the nickel targets (Table 26).
  • the proton bombardment of the copper and zinc impurities can produce the Zn-65 (i.e., 65 Cu(p,n) 65 Zn, 66 Zn(p,d) 65 Zn), and both reactions have good cross sections near 13 MeV and high natural abundancies (Cu-65: 30.9%, Zn-66: 27.7%).
  • the Ga-67 could be the result of the 67 Zn(p,n) 67 Ga or 68 Zn(p,2n) 67 Ga reactions during bombardment of the zinc impurity which have favorable cross sections in the beam energy range passing through the target with natural abundances of Zn-67 and Zn-68 being 4.0% and 18.5% respectively.
  • Bi-206 is produced by the favorable (p,n) and (p,2n) nuclear reactions for Pb-206 and Pb-207 respectively (natural abundancies: Pb-206: 24.1%, Pb-207: 22.1%).
  • the Au-196 could be produced by the 197 Au(p,d) 196 Au reaction when the proton beam strikes the gold plating that the nickel is played on to (Natural Abundance: Au-197: 100%). A high presence of Au-196 impurities could indicate that the proton beam is not well aligned and is striking sections of the target not plated with nickel.
  • the Cu-64 yields do continuously increase as the bombardment time approaches 24 h, but the yield increase diminishes at longer beam times as the Cu-64 decay rate approaches the production rate.
  • Co-61 one of the main impurities produced during the Ni-64 runs, reaches its saturation activity at roughly 13 h of beam time. Since Co-61 has a half-life of only 1.65 hr, it takes less time for the decay rate to equal the production rate. Due to the discrepancies between Cu-64 and Co-61, increasing the bombardment time beyond 13 hr will lead to increases in the Cu-64 activity produced without also drastically increasing the Co-61 activity produced. 116 100563663.1 Atty. Docket No.
  • the maximum Cu-64 saturation yields increases with the plating mass for the three plating masses simulated (i.e., 0.50, 0.65, and 0.80 g of enriched Ni-64).
  • the optimum beam energies for producing Cu-64 are between roughly 5 and 16 MeV with a maximum near 10 MeV. If the target is not thick enough and the beam energy is too high, the protons will escape out the back of the target before reaching the optimum beam energy for the 64 Ni(p,n) 64 Cu reaction.
  • Co-61 is the isotopic impurity with the highest saturation activity as it is produced by the 64 Ni(p, ⁇ ) 61 Co reaction and Ni-64 is the most prevalent isotope in the enriched Ni-64 target.
  • the Co-61 saturation yield also increases. As the saturation yield for Co-61 starts to increase more rapidly above beam energies of 10 MeV, using a lower beam energy could reduce the production of Co-61 during bombardment.
  • ICP-OES results for the strip solution from each IKON bombardment are included in Table 29. Data for Cu, Ni, and common elemental impurities are included. 120 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 Table 29: Strip Solution ICP Values and Calculated Nickel Recoveries and low ( ⁇ 10 ppm) for each of the bombardments. Low levels of Cu detected are expected for short duration bombardments and support that the gold-plated target remained integral throughout the bombardment and target processing.
  • Statement 1 A composition comprising from 15 Ci to 110 Ci of copper-64 ( 64 Cu) and having a specific activity from 50 mCi to 3850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 2 A composition comprising from 50 Ci to 100 Ci of 64 Cu and having a specific activity from 50 mCi to 3800 mCi 64 Cu/ ⁇ g Cu.
  • Statement 3 A composition comprising from 25 Ci to 75 Ci of 64 Cu and having a specific activity from 50 mCi to 3800 mCi 64 Cu/ ⁇ g Cu.
  • Statement 4 A composition comprising from 17 Ci to 20 Ci of 64 Cu and having a specific activity from 50 mCi to 3800 mCi 64 Cu/ ⁇ g Cu.
  • Statement 5 A composition comprising from 25 Ci to 50 Ci of 64 Cu and having a specific activity from 50 mCi to 3800 mCi 64 Cu/ ⁇ g Cu. 123 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1
  • Statement 6 A composition comprising from 20 Ci to 110 Ci of 64 Cu and having a specific activity from 50 mCi to 3800 mCi 64 Cu/ ⁇ g Cu.
  • Statement 7 A composition comprising from 25 Ci to 110 Ci of 64 Cu and having a specific activity from 50 mCi to 3800 mCi 64 Cu/ ⁇ g Cu.
  • Statement 8 The composition of statement 1, wherein the composition comprises a radiolytic purity for 64 Cu of ⁇ 98.9% and a radiolytic purity of 61 Co of ⁇ 1.0%.
  • Statement 9 The composition of statement 8, wherein the composition comprises a radiolytic purity for 64 Cu of approximately 100.0% and a radiolytic purity of 61 Co of approximately 0.0%.
  • Statement 10 The composition of statement 1, wherein the composition has a total content of less than or equal to 20 ⁇ g/mL of elemental copper.
  • Statement 11 The composition of statement 1, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of cobalt.
  • Statement 12 The composition of statement 1, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of iron.
  • Statement 13 The composition of statement 1, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of nickel.
  • Statement 14 The composition of statement 1, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of lead.
  • Statement 15 The composition of statement 1, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of zinc.
  • Statement 16 The composition of statement 1, wherein the composition has a total content of trace metals of less than about 5 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, gallium, germanium, zinc, and combinations thereof.
  • Statement 17 The composition of statement 1, wherein the composition comprises a solution of hydrochloric acid (HCl) having a molarity of about 0.001 M to about 3 M. 124 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1
  • Statement 18 The composition of statement 17, wherein the molarity of the HCl is about 0.05 M.
  • Statement 19 The composition of statement 17, wherein the molarity of the HCl is about 0.5 M.
  • Statement 20 The composition of statement 1, wherein the 64 Cu exists as [ 64 Cu]CuCl2.
  • Statement 21 The composition of statement 1, wherein the composition further comprises a chelating agent or a bifunctional chelating agent in which the 64 Cu is coordinated therein, and the chelating agent or the bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.
  • Statement 22 The composition of statement 21, wherein the chelating agent is DOTA or DOTAGA.
  • Statement 23 The composition of statement 1, wherein the composition is suitable for administration to a human subject in need thereof once divided into a smaller aliquot.
  • Statement 24 A process for preparing copper-64 ( 64 Cu) from nickel-64 ( 64 Ni), the process comprising: (a) bombarding a cyclotron target comprising 64 Ni with a proton beam to generate a bombarded target; (b) stripping the bombarded target with a volume of hydrochloric acid (HCl) having a molarity of about 6 M to about 12.1 M to form a strip solution comprising 64 Ni, 64 Cu, 61 Co, and one or more other metals; and (c) purifying the 64 Cu from the strip solution by: (i) passing the strip solution through a first column comprising an extraction resin connected in series to a second column comprising an ion exchange resin such that the one or more other metals binds to the extraction resin in the first column, 64 Cu and 61 Co bind to the ion exchange resin in the second
  • Statement 25 The process of statement 24, wherein the proton beam at (a) has one or more of (i) an energy of about 12 MeV to about 30 MeV, optionally wherein the energy is about 13 MeV; and (ii) a current of 100-1500 ⁇ A x hr, optionally wherein the current is 139, 750, or 1500 ⁇ A x hr.
  • Statement 26 The process of statement 24, wherein the bombarding at (a) proceeds for about 1 h to about 24 h, and the bombarded target comprises from about 2 Ci to about 110 Ci of 64 Cu at the end of bombardment (EOB).
  • Statement 27 The process of statement 24, wherein after about 2 h to about 4 h of bombarding at (a), the bombarded target comprises from about 2 Ci to about 25 Ci of 64 Cu at EOB.
  • Statement 28 The process of statement 24, wherein after about 6 h of bombarding at (a), the bombarded target comprises from about 5 Ci to about 9 Ci of 64 Cu at EOB.
  • Statement 29 The process of statement 24, wherein after about 8 h to about 12 h of bombarding at (a), the bombarded target comprises from about 4 Ci to about 15 Ci of 64 Cu at EOB. 126 100563663.1 Atty. Docket No.
  • Statement 30 The process of statement 24, wherein the stripping at (b) comprises contacting the bombarded target with 9 M HCl, and the stripping at (b) is conducted at a temperature of about 65 ⁇ C to about 100 ⁇ C.
  • Statement 31 The process of statement 24, wherein the extraction resin in the first column at (c)(i) comprises tributylphosphate as a functional group, and the ion exchange resin in the second column at (c)(i) comprises a tertiary amine as a functional group.
  • Statement 32 The process of statement 24, wherein the rinsing at (c)(ii) comprises 9 M HCl.
  • Statement 33 The process of statement 24, wherein the first and second flow-through fractions are combined as a 64 Ni recovery fraction.
  • Statement 34 The process of statement 33, wherein at least 90% of the target 64 Ni is recovered in the 64 Ni recovery fraction.
  • Statement 35 The process of statement 24, wherein the rinsing at (c)(iii) comprises 4 M HCl, and the rising at (c)(iv) comprises 5 M NaCl in 0.05 M HCl or the rinsing at (c)(iv) comprises 4 M HCl.
  • Statement 36 The process of statement 24, wherein the 64 Cu is eluted at (c)(v) with 0.05 M HCl.
  • Statement 37 The process of statement 24, wherein at least 80% of the 64 Cu present in the strip solution is recovered in the product fraction comprising 64 Cu.
  • Statement 38 The process of statement 24, wherein the product fraction comprising 64 Cu comprises from about 2 Ci to about 110 Ci of 64 Cu and has a specific activity up to about 3800 mCi 64 Cu/ ⁇ g Cu.
  • Statement 39 The process of statement 24, wherein the product fraction comprising 64 Cu has a total content of trace metals of less than about 5 ppm, the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc. 127 100563663.1 Atty. Docket No.
  • Statement 43 The composition of statement 1, wherein the composition has a total content of trace metals of less than about 5 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.
  • Statement 44 The composition of statement 1, wherein the composition has a total content of trace metals of less than about 3 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, and zinc.
  • Statement 45 The composition of statement 1, wherein the composition has a total content of less than about 6 parts per million (ppm) of copper-67 ( 67 Cu).
  • Statement 46 The composition of statement 1, wherein the composition has a total content of less than about 5 parts per million (ppm) of 67 Cu.
  • Statement 47 The composition of statement 1, wherein the composition has a total content of less than about 3 parts per million (ppm) of 67 Cu.
  • Statement 48 The composition of statement 1, wherein the composition has a total content of less than about 1 parts per million (ppm) of 67 Cu.
  • Statement 49 The composition of statement 1, wherein the composition has a total content of less than about 6 parts per million (ppm) of zinc-68 ( 68 Zn).
  • Statement 50 The composition of statement 1, wherein the composition has a total content of less than about 5 parts per million (ppm) of 68 Zn.
  • Statement 51 The composition of statement 1, wherein the composition has a total content of less than about 3 parts per million (ppm) of 68 Zn. 129 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1
  • Statement 52 The composition of statement 1, wherein the composition has a total content of less than about 1 parts per million (ppm) of 68 Zn.
  • Statement 53 The composition of statement 1, wherein the composition has a total content of less than about 6 parts per million (ppm) of any atom or isotope with a mass number of 67 or greater.
  • Statement 54 The composition of statement 1, wherein the composition has a total content of less than about 5 parts per million (ppm) of any atom or isotope with a mass number of 67 or greater.
  • Statement 55 The composition of statement 1, wherein the composition has a total content of less than about 3 parts per million (ppm) of any atom or isotope with a mass number of 67 or greater.
  • Statement 56 The composition of statement 1, wherein the composition has a total content of less than about 1 parts per million (ppm) of any atom or isotope with a mass number of 67 or greater.
  • Statement 57 The composition of statement 1, wherein the composition has a total content of less than about 6 parts per million (ppm) of any atom or isotope with a mass number of 68 or greater.
  • Statement 58 The composition of statement 1, wherein the composition has a total content of less than about 5 parts per million (ppm) of any atom or isotope with a mass number of 68 or greater.
  • Statement 59 The composition of statement 1, wherein the composition has a total content of less than about 3 parts per million (ppm) of any atom or isotope with a mass number of 68 or greater.
  • Statement 60 The composition of statement 1, wherein the composition has a total content of less than about 1 parts per million (ppm) of any atom or isotope with a mass number of 68 or greater.
  • Statement 61 The composition of statement 1, wherein the composition has an absence of zinc-based target source materials. 130 100563663.1 Atty. Docket No.
  • Statement 62 The composition of statement 1, wherein the composition has a total content of trace metals of 0 ppm Au, 0 ppm Hg, ⁇ 0.02 ppm Co, ⁇ 0.2 ppm Fe, ⁇ 0.4 ppm Pb, ⁇ 0.5 ppm Ni, ⁇ 0.6 ppm Cu, and ⁇ 1.5 ppm Zn.
  • Statement 63 The composition of statement 1, wherein the composition comprises a solution of hydrochloric acid (HCl) having a molarity of about 0.001 M to about 3 M.
  • HCl hydrochloric acid
  • Statement 64 The composition of statement 1, wherein the 64 Cu exists as [ 64 Cu]CuCl2.
  • Statement 65 The composition of statement 1, wherein the composition further comprises a chelating agent or a bifunctional chelating agent in which the 64 Cu is coordinated therein, and the chelating agent or the bifunctional chelating agent is a macrocyclic compound, a bridged macrocyclic compound, a bicyclic compound, or an acyclic compound.
  • Statement 66 The composition of statement 65, wherein the bifunctional chelating agent is DOTA.
  • Statement 67 The composition of statement 65, wherein the chelating agent is DOTAGA.
  • Statement 68 The composition of statement 1, wherein the radionuclidic purity of the 64 Cu is greater than 98.5%.
  • Statement 69 The composition of statement 1, wherein the radionuclidic purity of the 64 Cu is greater than 99.0%.
  • Statement 70 The composition of statement 1, wherein the radionuclidic purity of the 64 Cu is greater than 99.5%.
  • Statement 71 The composition of statement 1, wherein the composition comprises chemical and radionuclidic purities suitable for positron emission tomography (PET). 131 100563663.1 Atty. Docket No.
  • Statement 72 A composition comprising copper-64 ( 64 Cu) in a single dose vial suitable for administration to a human patient in need thereof, wherein the composition is aliquoted from the composition of any of the previous statements.
  • Statement 73 A composition comprising 35 MBq to 40 MBq of copper- 64 ( 64 Cu) per 1 mL of the composition in a single dose vial suitable for administration to a human patient in need thereof, wherein the composition is aliquoted from the composition of any of the previous statements.
  • Statement 74 A composition comprising 145 MBq to 150 MBq of copper-64 ( 64 Cu) in a single dose vial suitable for administration to a human patient in need thereof, wherein the composition is aliquoted from the composition of any of the previous statements.
  • Statement 75 A composition comprising from 16 Ci to 30 Ci, 20 Ci to 30 Ci, or 25 Ci to 30 Ci of copper-64 ( 64 Cu).
  • Statement 76 A composition comprising from 15 Ci to 110 Ci, 16 Ci to 110 Ci, 17 Ci to 110 Ci, 18 Ci to 110 Ci, 19 Ci to 110 Ci, 20 Ci to 110 Ci, 21 Ci to 110 Ci, 22 Ci to 110 Ci, 23 Ci to 110 Ci, 24 Ci to 110 Ci, 25 Ci to 110 Ci, 26 Ci to 110 Ci, 28 Ci to 110 Ci, 29 Ci to 110 Ci, 30 Ci to 110 Ci, 31 Ci to 110 Ci, 32 Ci to 110 Ci, 33 Ci to 110 Ci, 34 Ci to 110 Ci, 35 Ci to 110 Ci, 36 Ci to 110 Ci, 37 Ci to 110 Ci, 38 Ci to 110 Ci, 39 Ci to 110 Ci, or 40 Ci to 110 Ci of copper-64 ( 64 Cu).
  • Statement 77 A composition comprising ⁇ 17.5 Ci, ⁇ 20 Ci, ⁇ 22.5 Ci, ⁇ 25 Ci, ⁇ 30 Ci, ⁇ 35 Ci, ⁇ 40 Ci, ⁇ 45 Ci, ⁇ 50 Ci, ⁇ 55 Ci, ⁇ 60 Ci, ⁇ 65 Ci, ⁇ 70 Ci, ⁇ 75 Ci, ⁇ 80 Ci, ⁇ 85 Ci, ⁇ 90 Ci, ⁇ 95 Ci, ⁇ 100 Ci, ⁇ 105 Ci, or ⁇ 100 Ci of copper-64 ( 64 Cu).
  • Statement 78 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 10 mCi to 3850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 79 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 25 mCi to 3850 mCi 64 Cu/ ⁇ g Cu. 132 100563663.1 Atty. Docket No. 089027- 832320 Client’s Ref.: C-US-009 WO1 [00431]
  • Statement 80 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 25 mCi to 6850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 81 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 25 mCi to 9850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 82 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 25 mCi to 12850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 83 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 50 mCi to 3850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 84 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 50 mCi to 6850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 85 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 50 mCi to 9850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 86 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 50 mCi to 12850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 87 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 100 mCi to 3850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 88 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 100 mCi to 6850 mCi 64 Cu/ ⁇ g Cu. 133 100563663.1 Atty. Docket No.
  • Statement 89 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 100 mCi to 9850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 90 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 100 mCi to 12850 mCi 64 Cu/ ⁇ g Cu.
  • Statement 91 A composition according to any of the previous statements, wherein the composition comprises a specific activity from 10 mCi to 100 mCi, 10 mCi to 200 mCi, 10 mCi to 300 mCi, 10 mCi to 400 mCi, 10 mCi to 500 mCi, 10 mCi to 600 mCi 64 Cu/ ⁇ g, 10 mCi to 700 mCi, 10 mCi to 800 mCi, 10 mCi to 900 mCi, or 10 mCi to 1000 mCi 64 Cu/ ⁇ g Cu.
  • Statement 92 A composition according to any of the previous claims, wherein the composition comprises a radiolytic purity for 64 Cu of ⁇ 95.0%, ⁇ 96.0%, ⁇ 97.0%, ⁇ 98.0%, ⁇ 99.0%, ⁇ 99.5%, or ⁇ 99.0%.
  • Statement 93 A composition according to any of the previous statements, wherein the composition comprises a radiolytic purity for 64 Cu of ⁇ 95.0%, ⁇ 96.0%, ⁇ 97.0%, ⁇ 98.0%, ⁇ 99.0%, ⁇ 99.5%, or ⁇ 99.0%, and a radiolytic purity of 61 Co of ⁇ 1.0%.
  • Statement 94 A composition according to any of the previous statements, wherein the composition comprises a radiolytic purity for 64 Cu of ⁇ 98.9% and a radiolytic purity of 61 Co of ⁇ 1.0%.
  • Statement 95 A composition according to any of the previous statements, wherein the composition comprises a radiolytic purity for 64 Cu of approximately 100.0% and a radiolytic purity of 61 Co of approximately 0.0%.
  • Statement 96 A composition according to any of the previous statements, wherein the composition has a total content of less than or equal to 20 ⁇ g/mL of elemental copper. 134 100563663.1 Atty. Docket No.
  • Statement 97 A composition according to any of the previous statements, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of cobalt.
  • Statement 98 A composition according to any of the previous statements, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of iron.
  • Statement 99 A composition according to any of the previous statements, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of nickel.
  • Statement 100 A composition according to any of the previous statements, wherein the composition of claim 1, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of lead.
  • Statement 101 A composition according to any of the previous statements, wherein the composition has a total content of less than or equal to 1 ⁇ g/mL of zinc.
  • Statement 102 A composition according to any of the previous statements, wherein the composition has a total content of trace metals of less than about 5 parts per million (ppm), the trace metals being cobalt, copper, gold, iron, lead, mercury, nickel, gallium, germanium, zinc, and combinations thereof.
  • ppm parts per million
  • Statement 103 A composition according to any of the previous statements, wherein the composition comprises a solution of hydrochloric acid (HCl) having a molarity of about 0.001 M to about 3 M.
  • Statement 104 A composition according to any of the previous statements, wherein the molarity of the HCl is about 0.05 M.
  • Statement 105 A composition according to any of the previous statements, wherein the molarity of the HCl is about 0.5 M.
  • Statement 106 A composition according to any of the previous statements, wherein the 64 Cu exists as [ 64 Cu]CuCl2. 135 100563663.1 Atty. Docket No.
  • Statement 107 A composition according to any of the previous statements, wherein the 64 Cu is isolated from an enriched Ni-64 target bombarded with a 13 MeV proton beam at 150-375 ⁇ A.
  • Statement 108 A composition according to any of the previous statements, wherein the 64 Cu is isolated from a target comprising a plating area ⁇ 20 cm 2 , ⁇ 21 cm 2 , ⁇ 22 cm 2 , ⁇ 23 cm 2 , ⁇ 24 cm 2 , or ⁇ 25 cm 2 .
  • Statement 109 A composition according to any of the previous statements, wherein the 64 Cu is isolated from a target comprising plated Ni-64 masses of 550 – 750 mg.
  • Statement 110 A composition according to any of the previous statements, wherein the composition is homogeneous.
  • Statement 111 A composition according to any of the previous statements, wherein the 64 Cu is produced by one continuous cyclotron bombardment (i.e., a single cyclotron run).
  • Statement 112 A composition according to any of the previous statements, wherein the 64 Cu is produced in a single location. 136 100563663.1

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Abstract

L'invention concerne des compositions comprenant des teneurs élevées en cuivre-64 à activité spécifique élevée, et procédé de préparation desdites compositions. Les compositions comprennent d'environ 2 Ci à environ 110 Ci, environ 15 Ci à environ 110 Ci, ou environ 20 Ci à environ 110 Ci de cuivre-64 isolé et ont des activités spécifiques d'environ 50 mCi à environ 3800 mCi de cuivre-64 par microgramme de cuivre. Les procédés de préparation desdites compositions consistent à bombarder une cible de nickel-64 avec une basse-moyenne énergie, un faisceau de protons à courant élevé, de basse énergie, et à purifier le cuivre-64 présent dans d'autres métaux par un procédé comprenant une chromatographie par échange d'ions ou un procédé comprenant une combinaison d'une chromatographie par extraction et d'une chromatographie par échange d'ions.
PCT/US2024/060406 2024-05-31 2024-12-16 Compositions de cuivre-64 et procédés de purification pour la préparation de nouvelles compositions de cuivre-64 Pending WO2025250184A1 (fr)

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US18/745,888 US20250197238A1 (en) 2023-06-16 2024-06-17 Copper-64 compositions and purification processes for the preparation of novel copper-64 compositions
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5619545A (en) * 1994-01-28 1997-04-08 Mallinckrodt Medical, Inc. Process for purification of radioiodides
US20220118120A1 (en) * 2019-01-30 2022-04-21 Technische Universität München Cancer diagnostic imaging agents
US20230165979A1 (en) * 2020-05-06 2023-06-01 Cornell University Copper-containing theragnostic compositions and methods of use
US20230402199A1 (en) * 2020-09-03 2023-12-14 Curium Us Llc Purification process for the preparation of non-carrier added copper-64

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5619545A (en) * 1994-01-28 1997-04-08 Mallinckrodt Medical, Inc. Process for purification of radioiodides
US20220118120A1 (en) * 2019-01-30 2022-04-21 Technische Universität München Cancer diagnostic imaging agents
US20230165979A1 (en) * 2020-05-06 2023-06-01 Cornell University Copper-containing theragnostic compositions and methods of use
US20230402199A1 (en) * 2020-09-03 2023-12-14 Curium Us Llc Purification process for the preparation of non-carrier added copper-64

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