WO2024253964A2 - Cyclotron compact 7 mev à 11 mev à des fins de production d'isotopes médicaux - Google Patents

Cyclotron compact 7 mev à 11 mev à des fins de production d'isotopes médicaux Download PDF

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WO2024253964A2
WO2024253964A2 PCT/US2024/031964 US2024031964W WO2024253964A2 WO 2024253964 A2 WO2024253964 A2 WO 2024253964A2 US 2024031964 W US2024031964 W US 2024031964W WO 2024253964 A2 WO2024253964 A2 WO 2024253964A2
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cyclotron
radiochemical
producing
mev
charged particles
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WO2024253964A3 (fr
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Manny R. Subramanian
Richard Johnson
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Best Abt Inc
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Best Abt Inc
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    • 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

  • the present invention relates generally to cyclotrons and particularly to a compact, self- shielded, high energy 7 MeV to 11 MeV having a beam current up to 100 microAmperes cyclotron system for medical isotope and biomarker production including clinical and research applications.
  • Cyclotrons are used to generate high energy charged particle beams for purposes such as nuclear physics research and medical treatments.
  • One area where cyclotrons have found particular utility is in the generation of radiopharmaceuticals, also known as biomarkers, for medical diagnosis by such techniques as positron emission tomography (PET).
  • PET positron emission tomography
  • a conventional cyclotron involves a substantial investment, both in monetary and building resources.
  • An example of one of the more compact conventional cyclotrons used for radiopharmaceutical production is the Eclipse RD.
  • the self-shielded version of the Eclipse RD can be installed in a facility without a shielded vault.
  • the minimum room size for housing the Eclipse RD is 7.31 mx7.01 mx3 m (24 ftx23 ftxlO ft).
  • the cyclotron room includes a concrete pad with a minimum thickness of 36 cm (14 in).
  • the power requirements often involve a dedicated and substantial electrical power system.
  • the minimum electrical service required for the Eclipse RD is a 208 ( ⁇ 5%) VAC, 150 A, 3-phase service.
  • a biomarker is used to interrogate a biological system and can be created by
  • PET positron-emission tomography
  • PET provides information not available from traditional imaging technologies, such as magnetic resonance imaging (MRI), computed tomography (CT) and ultrasonography, which image the patient's anatomy rather than physiological images.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • ultrasonography ultrasonography
  • Cyclotrons have been known for many years.
  • a cyclotron is one type of particle accelerator in which charged particles are accelerated through a substantially spiral path using the forces of electrical potential and magnetic fields.
  • the first cyclotron was invented by Ernest O. Lawrence in 1929-1930 at the University of California, Berkeley, for which he was awarded the Nobel Prize in Physics in 1939.
  • a cyclotron accelerates a charged particle beam using a high frequency alternating voltage which is applied between two hollow "D"-shaped sheet metal electrodes called “dees” inside a vacuum chamber.
  • the path of the accelerated particle is then bent by a magnetic field into a spiral path (due to the Lorentz force perpendicular' to their direction of motion), which tends to cause the particle to be directed back across the gap.
  • the particles are accelerated with each crossing of the gap, thereby increasing the radius of the spiral path of the accelerated particles.
  • a small voltage on a metal plate deflects the beam and hits a target located at the exit point at the rim of the chamber.
  • U.S. Patent Nos. 7,476,883 and 8,080,815 to Ronald Nutt, and U.S. Patent No. 11,135,321B2 to Khachaturian et al., incorporated herein by reference in their entirety disclose prior-art biomarker generator cyclotron systems.
  • the prior art cyclotron described in U.S. Patent No. 7,476,883 to Ronal Nutt discloses a two-pole cyclotron 10, which includes a magnet system having four magnet poles, each defining a wedge shape.
  • the upper magnet poles 26, 28 protrude downward from the upper magnet yoke 54, toward the lower magnet poles 30, 32 which protrude upward from the lower magnet yoke 56.
  • the magnetic field which is represented by the arrows 58, is perpendicular to the longitudinal plane of the “dees” and, therefore, is perpendicular also to the electric field generated by the alternating high voltage.
  • the magnetic field exerts a force that is perpendicular both to the direction of motion of the charged particle and to the magnetic field.
  • a charged particle in a magnetic field having a constant strength undergoes circular' motion if the area defined by the magnetic field is sufficiently large.
  • the diameter of the circular path of the charged particle is dependent on the velocity of the charged particle and on the strength of the magnetic field. It is prudent to note that a magnetic field causes a charged particle to change direction continuously; however, it does not alter the velocity of a charged particle, hence the energy of the charged particle is unaffected.
  • the magnet poles are often called “hills,” and the hills define recesses that are often called “valleys.” In FIG. 1, all four of the hills 26, 28, 30, 32 and two of the four valleys 34, 36 are visible.
  • the beam 40 during acceleration, is exposed alternately to the strong and weak magnetic fields defined respectively by the hills and valleys along its path to the extraction radius. As the beam 40 passes through each hill region, it bends sharply due to the effect of the strong magnetic field. While in the valley regions, however, the beam trajectory is more nearly a straight path toward the next hill region.
  • This alternating magnetic field provides strong vertical focusing forces to beam particles straying from the median plane during acceleration. These focusing forces direct straying particles back toward the median plane, promoting high beam extraction efficiencies.
  • the RF system of a cyclotron supplies an alternating high voltage potential to the dees.
  • each of the two dees 12, 14 is mounted in a valley region.
  • the beam 40 of positively-charged particles gains energy by being attracted by the dee when the dee has a negative charge, and then by being repelled from the dee as the dee changes to a positive charge.
  • a charged particle within the beam 40 passes through both dees 12, 14 in the course of a single orbit, that charged particle undergoes two increments of acceleration per orbit.
  • the beam 40 of charged particles gains a known, fixed quantity of energy, and its orbital radius increases in predetermined fixed increments until it reaches the extraction radius, which corresponds to the extraction energy of the beam.
  • the ion source system 80 is required for generating the charged particles for acceleration.
  • PAG Penning Ion Gauge
  • H + proton
  • This ion source system ionizes hydrogen gas using a strong electric current.
  • the ionized hydrogen gas forms plasma, from which protons (H + ions) are extracted for acceleration using a bias voltage.
  • Target systems are well known in the prior art and they generally operate as follows:
  • the beam exits the magnetic field 58 at the predetermined location 90 and enters the accelerator beam tube 92, which is aligned with the target entrance 94.
  • a collimator 96 which consists of a carbon disk defining a central hole, is mounted at the target entrance 94, and as the beam 40 passes through the collimator 96, the collimator 96 refines the profile of the beam.
  • the beam 40 then passes through the target window 98, which consists of an extremely thin sheet of foil made of a high-strength, non-magnetic material such as molybdenum.
  • the beam 40 encounters the target substance 100, which is positioned behind the target window 98.
  • the beam 40 bombards the target substance 100, which may comprise a gas, a liquid, or a solid, generating the desired radioisotope through a nuclear reaction.
  • Embodiments include apparatuses, systems and methods related to the use of a compact, self-shielded, proton cyclotron for producing a radiochemical.
  • the compact, selfshielded cyclotron system for producing a radiochemical includes a cyclotron for generating a beam of charged particles having a beam envelope consisting essentially of particles having an energy in the range of 7 MeV to 11 MeV; an accelerator for directing the beam of charged particles along a path; a plurality of targets positioned within or outside of said cyclotron, said plurality of targets positioned in the path of the beam of charged particles; said targets comprising a target substance having a composition selected for producing a radioactive substance during interaction with the beam of charged particles; wherein said target substance is in a solid, a gaseous or a liquid state; a radiochemical synthesis subsystem integrated with or in communication with said cyclotron, said radiochemical synthesis subsystem having one or more of a microreactor or a microfluidic chip, wherein
  • the radioactive substance is a positron-emitting substance selected from the group consisting of F-18, C-ll, N-13, Ga-68, 0-15, Cu-64, Ga 67, In 111, 1-123, Zr-89, Tc-99m, Pd-103 and Ac-225.
  • the compact, self-shielded cyclotron system includes a method for producing single or multiple doses of a PET biomarker.
  • the method for producing single or multiple doses of a PET biomarker includes the steps of: (a) providing a compact cyclotron system for generating a beam of charged particles, the beam consisting essentially of protons having an energy in a range of 7 MeV to 11 MeV; (b) generating the beam of charged particles consisting essentially of a beam of protons using a particle accelerator associated with the cyclotron system; (c) bombarding one or more target substances with the beam consisting essentially of protons to produce one or more radioactive substances corresponding to one or more of the target substances; (d) providing a radiochemical synthesis subsystem having one or more of a microreactor or a microfluidic chip, said radiochemical synthesis subsystem for receiving the one or more radioactive substances, for receiving at least one reagent to synthesize the one or more radioactive substances, and for synthesizing from the
  • FIG. 1 is an exploded view of a diagrammatic illustration of certain components of a prior art biomarker generator (BG) cyclotron.
  • BG biomarker generator
  • FIG. 2 schematic illustrating an overview of an embodiment of the 7 MeV to 11 MeV cyclotron illustrating the proton cyclotron according to an embodiment of the present invention.
  • FIG. 3 is a schematic illustrating an embodiment of the 7 MeV to 11 MeV cyclotron having a beam envelope, a beam line and multiple internal and/or external targets according to an embodiment of the present invention.
  • FIG. 4 is a plan view of the biomarker generator (BG) cyclotron system with various components in the cyclotron room and the GMP room including a computer which controls the cyclotron and the radiopharmaceutical synthesis subsystem for producing the biomarker according to an embodiment of the present invention.
  • FIG. 5 is a block diagram of a biomarker generator system including the improved cyclotron described herein for producing a unit dose or multi-unit doses of a biomarker according to an embodiment of the present invention.
  • FIG. 6 is a flow diagram of an exemplary embodiment of a fully automated method for producing one unit dose or multi-unit doses of a biomarker using the improved and novel biomarker generator cyclotron system according to an embodiment of the present invention.
  • the present disclosure relates to apparatuses, systems and methods for the use of an improved, compact, self-shielded 7 MeV to 11 MeV proton cyclotron for producing radiochemicals or biomarkers for positron-emission tomography (PET)/computed tomography (CT) medical applications including research applications.
  • PET positron-emission tomography
  • CT computed tomography
  • An improved compact cyclotron system and a method suitable for efficiently producing short lived radiopharmaceuticals in unit dose and multi-unit doses is described in detail herein and illustrated in the accompanying figures.
  • the improved compact cyclotron system includes a particle accelerator and a radiopharmaceutical synthesis subsystem integrated with or in communication with the cyclotron, which are controlled by a computer.
  • the radiochemical synthesis subsystem of the improved compact cyclotron is a small volume chemical synthesis system comprising a microreactor and/or a microfluidic chip and optimized for synthesizing the radiochemical in quantities on the order of one unit dose or multi-unit doses allowing for significant reductions in the quantity of radioisotope required and in the processing time as compared to conventional radiopharmaceutical processing systems.
  • Embodiments are described of the compact, self-shielded cyclotron system for producing a radiochemical, said system includes a cyclotron for generating a beam of charged particles having a beam envelope consisting essentially of particles having an energy in the range of 7 MeV to 11 MeV; an accelerator for directing the beam of charged particles along a path; a plurality of targets positioned within or outside of said cyclotron, said plurality of targets positioned in the path of the beam of charged particles; said targets comprising a target substance having a composition selected for producing a radioactive substance during interaction with the beam of charged particles; wherein said target substance is in a solid, a gaseous or a liquid state; a radiochemical synthesis subsystem integrated with or in communication with said cyclotron, said radiochemical synthesis subsystem having one or more of a microreactor or a microfluidic chip, wherein said radiochemical synthesis subsystem for receiving the radioactive substance, for receiving at least one reagent to synthesize the radiochemical and
  • the self-shielded compact cyclotron system for producing a radiochemical can have a beam current in the range of about 1 to about 100 micro- Amperes.
  • the target includes a plurality of liquid internal targets positioned within the cyclotron or an external solid or gaseous target positioned external to the cyclotron.
  • the compact cyclotron system can further include a beam collimator to direct the beam of charged particles to a solid or a gaseous target positioned external to or outside the cyclotron.
  • the beam of charged particles consists essentially of protons having an energy of approximately 9 MeV to 11 MeV.
  • the cyclotron system further includes a shield positioned externally to surround the cyclotron to reduce a radiation field generating from the beam of charged particles to an acceptable level, such as of less than 1 millirem/hr. Additionally, in some instances, the cyclotron can be modified to produce energies greater than 11 MeV up to 15 MeV. Such modifications will readily be apparent to those skilled in the art, using the guidance of the instant disclosure.
  • the compact self-shielded cyclotron system for producing a radiochemical further includes a computer controller system configured in communication with the cyclotron and the radiochemical synthesis subsystem to control the cyclotron to generate and deliver the beam of charged particles for irradiation of the target and to control the radiochemical synthesis subsystem.
  • the computer controller can move and position the target in the path of the beam of charged particles.
  • the computer controller system can include a user interface to enable selection of a radiopharmaceutical for radiochemical synthesis by the radiochemical synthesis subsystem, wherein the selection can be for the production of FDG-F18 or NH2-N13 radiochemical, for example.
  • the compact, self-shielded cyclotron system for producing a radiochemical includes a permanent magnet for directing the beam as the beam is being accelerated by the accelerator.
  • the radioactive substance includes a radioisotope that emits positrons, which includes a (PET) biomarker.
  • the (PET) biomarker can be selected from the group consisting of F-18, C-l l, N-13, Ga-68, 0-15, Cu-64, Ga 67, In 111, I- 123, Zr-89, Tc-99m, Pd-103 and Ac-225, for example.
  • the method for producing single or multiple doses of one or more (PET) biomarkers includes the steps of: (a) providing a compact cyclotron system for generating a beam of charged particles, the beam consisting essentially of protons having a minimum energy between 7 MeV to 11 MeV; (b) generating the beam of charged particles consisting essentially of a beam of protons using a particle accelerator associated with the cyclotron system; (c) bombarding one or more target substances with the beam consisting essentially of protons to produce one or more radioactive substances corresponding to one or more of the target substances; (d) providing a radiochemical synthesis subsystem having one or more of a microreactor or a microfluidic chip, said radiochemical synthesis subsystem for receiving the one or more radioactive substances, for receiving at least one reagent to synthesize the one or more radio
  • a computer controller controls the synthesis of one or more unit doses of the one or more (PET) biomarkers.
  • the radioactive substance is a positron-emitting substance selected from the group consisting of F-18, C-ll, N-13, Ga-68, 0-15, Cu-64, Ga 67, In-111, I- 123, Zr-89, Tc-99m, Pd-103 and Ac-225, for example.
  • the biomarker is selected from the group consisting of 18FDG, Nal 8F, 18F-MIS0, 18FLT, 18F- Choline, 18F-D0PA and 18F-PSMA, for example.
  • the bombarding of the one or more target substances can include placing the one or more target substances internally within the compact cyclotron system or placing the one or more target substances externally to the compact cyclotron system.
  • the cyclotron desirably has a beam current in the range of about 1 to about 100 micro- Amperes, for example.
  • MeV refers to one mega electron volt, or one million electron volts.
  • One MeV is typically the amount of energy acquired by a charged particle with one electron charge in passing through a potential difference of one million volts in a vacuum.
  • patient refers to any human or animal subject, particularly including all mammals.
  • radiochemical is intended to encompass any organic or inorganic compound comprising a covalently-attached radioisotope (e.g., 2-deoxy-2-[ 18 F]fluoro-D-glucose ([18F]FDG)), any inorganic radioactive ionic sodium fluoride solution (e.g., Na[ 18 F]F ionic solution), or any radioactive gas (e.g., “[ n C]”), particularly including radioactive molecular imaging probes intended for administration to a patient or subject (e.g., by inhalation, ingestion, or intravenous injection) for human imaging purposes, such probes are referred to also in the art as radiopharmaceuticals, radiotracers, or radioligands.
  • a covalently-attached radioisotope e.g., 2-deoxy-2-[ 18 F]fluoro-D-glucose ([18F]FDG)
  • any inorganic radioactive ionic sodium fluoride solution e.
  • 18F-MISO refers to [ IS F] fluoro-2-hydroxypropyl)-2- nitroimidazole.
  • 18FLT refers to Fluorothymidine F-18, which is a tumor- specific PET tracer and radiopharmaceutical.
  • 18F-choline refers to a radioactive substance with the chemical formula 18F-[(CH 3) 3NCH 2CH 2OH],
  • 18F-DOPA refers to Fluoro-dihydroxyphenylalanine routinely used in Positron Emission Computed Tomography (PET/CT) in oncologic and nononcologic imaging.
  • 18F-PSMA refers to 18F- Prostate-specific membrane antigen.
  • NH2-N13 is a modified ammonia that has a 13N isotope as the nitrogen atom.
  • reagent is a substance used in synthesizing the biomarker because of the chemical or biological activity of the substance.
  • a reagent include a solvent, a catalyst, an inhibitor, a biomolecule, and a reactive precursor.
  • reactive precursor refers to an organic or inorganic non-radioactive molecule that, in synthesizing a biomarker or other radiochemical, is reacted with a radioactive isotope (radioisotope), typically by nucleophilic substitution, electrophilic substitution, or ion exchange.
  • radioactive isotope typically by nucleophilic substitution, electrophilic substitution, or ion exchange.
  • the nature of the reactive precursor varies and depends on the physiological process that has been selected for imaging.
  • Exemplary organic reactive precursors include sugars, amino acids, proteins, nucleosides, nucleotides, small molecule pharmaceuticals, and derivatives thereof.
  • synthesis refers to the production of the biomarker by the union of chemical elements, groups, or simpler compounds, or by the degradation of a complex compound, or both. Synthesis, therefore, includes any tagging or labeling reactions involving the radioisotope and any processes (e.g., concentration, evaporation, distillation, enrichment, neutralization, and purification) used in producing the biomarker or in processing the target substance for use in synthesizing the biomarker.
  • unit dose refers to the quantity of radioactivity, expressed in millicuries (mCi), which is administered for PET to a particular class of patient or subject.
  • mCi millicuries
  • a human adult generally requires a unit dose of biomarker in the range of approximately ten (10) mCi to approximately fifteen (15) mCi.
  • a unit dose for a small animal, such as a mouse may be only a few microcuries ( ,Ci).
  • a unit dose of biomarker necessarily comprises a unit dose of a radioisotope.
  • multi-dose refers to multiple unit doses of the biomarker.
  • microreactors and “microfluidic chips” refer broadly to small volume reaction systems including microscale, nanoscale, and Pico scale systems.
  • microreactor is a miniaturized reaction system fabricated, at least in part, using methods of microtechnology and precision engineering.
  • the first prototype microreactors for chemical processes, including chemical synthesis, were manufactured and tested in the early 1990s.
  • the characteristic linear dimensions of the internal structures of a microreactor, such as fluid channels, generally are in the nanometer to millimeter range.
  • the fluid channels in a microreactor typically have a diameter of between approximately a few nanometers and approximately a few millimeters.
  • a microreactor may include only one functional component, and that component may be limited to a single operation, such as mixing, heat exchange, or separation.
  • functional components include micropumps, micromixers, and micro heat exchangers. As more than one operation generally is necessary to perform even the simplest chemical process, more complex systems, sometimes referred to as integrated micro reaction systems, have been developed.
  • such a system includes at least several different functional components, and the configuration of such systems can vary significantly depending on the chemical process that the system is engineered to perform. Additionally, integrated micro reaction systems that include arrays of microreactors have been developed to provide continuous-flow production of chemicals.
  • microfluidic chips refers to fluidic devices that are analogous to electronic integrated circuits fabricated using large-scale integration. As is common in the terminology of emerging scientific or engineering disciplines, there is no unanimity on a definition of microfluidics, and there likely is at least some overlap between microfluidics and the discipline of micro reaction technology described previously.
  • a microfluidic system processes fluids on a chip that defines a fluidic circuit, where the chip is under digital control and the fluid processing is performed using the fluidic circuit, which includes at least one reaction channel, chamber, compartment, reservoir, vessel, or cleft having at least one cross-sectional dimension (e.g., diameter, depth, length, width, height) on the order of micrometers, nanometers, or even picometers for altering fluid behavior and, possibly, chemical behavior for the purpose of enhancing performance.
  • a microfluidic system enjoys the advantages inherent in a micro-reaction system that were set forth previously. At least some microfluidic systems can be thought of as including a fluidic chip that incorporates a microreactor.
  • an exemplary biomarker generator cyclotron system 100 such as a proton cyclotron system 100 such as for the production of a biomarker, has an energy typically in a range of from 7 MeV to 11 MeV and has a beam, the biomarker generator cyclotron system 100 being diagrammatically illustrated in FIG. 2.
  • the biomarker generator system 100 includes a compact cyclotron that integrates a cyclotron 104, which is self- shielded, and a target processing and synthesis system 114 or 112, which can be positioned next to the cyclotron 104.
  • the cyclotron 104 includes a proton ion source 101, which is accelerated by an accelerator 108 by magnets 106, 116 to form a proton beam envelope 102 which can be directed to multiple internal production targets 110 and 109, such as liquid targets 110 and 109, for example.
  • the compact cyclotron system can be positioned near a PET/CT imaging device for use “on demand”, for example.
  • FIG. 3 another embodiment of a cyclotron 200, of the present invention is schematically illustrated.
  • the hydrogen ion source 210 is accelerated using the magnet hills 202 in a RF cavity 204 forming a beam envelope 212 before being focused onto multiple beam targets 206 and 208 positioned opposite other targets 207 and 209, for example.
  • the beam envelope 212 can be directed, such as by using computer control or computer controls, into multiple beam lines to impact multiple targets, such as targets 207 and 209 simultaneously that can be in a liquid or a gaseous state, for example.
  • the targets 207 and 209 can access different portions of the beam envelope 212.
  • the internal target system can include a stainless steel tube having a target window opening centered in the path of the charged particle beam, such as illustrated in US Patent 8,080,815 B2 to Nutt, which is incorporated herein by reference in its entirety.
  • the beam energy typically can be in the range of 7 MeV to 11 MeV and, in some instances, the cyclotron can be modified, using the guidance of the instant disclosure, to produce energies greater than 11 MeV up to 15 MeV, for example, with varying beam currents of 1 to 100 micro- Amperes, depending on the desired radiochemical production target.
  • a single or multiple extraction from different sides of the cyclotron 200 can be configured for the cyclotron 200 to serve more than one beamline and be directed to single or multiple external targets simultaneously.
  • the beam line 214 can be extracted and focused using a collimator 213 at any extraction point on the side of the cyclotron 200 to bombard an external target 215 located outside of or externally to the cyclotron 200.
  • target irradiation stations can be placed in independent shielded compartments allowing service without disrupting cyclotron operation.
  • the inventive compact cyclotron system 200 has a dual capability of irradiating a plurality of targets positioned within or outside of the cyclotron 200 which can be in a gaseous, a liquid or a solid state for the production of a multitude of radioisotopes, simultaneously or non-simultaneously, including but not limited to F-18, C-l l, N-13, Ga-68, Zr-89, Tc-99m, C-l l, N-13, 0-15, Cu-64, Ga-67, In- 111, 1-123, AC- 225 and Pd-103, for example.
  • the typical dimensions of the exemplary cyclotron, such as the cyclotron 200, according to the present invention, can have a diameter of 49 inches and a height of 42 inches, lower shields, having a diameter of 8 feet and height of 27 inches, floor shielding having a diameter of 48 inches and height of 14 inches, and top movable shields having a diameter of 8 feet and height of 37 inches, for example.
  • the shield material can be made from ceramic/polymer composite material, for example, that can absorb all ionizing radiation.
  • the cyclotron, such as the cyclotron 200 can be placed near a PET/CT scan table in a hospital room or a clinic without causing harmful radiation problems.
  • FIG. 4 illustrates an embodiment of the improved biomarker generator system or cyclotron system 300, including a cyclotron 309 and one or more of a radiopharmaceutical micro-synthesis system 316 and a radiopharmaceutical macro-synthesis system 317.
  • the exemplary cyclotron 309 is a dual capability system capable of producing small scale as well as larger scale radiochemicals.
  • this inventive cyclotron system is housed in a cyclotron room (identified in FIG.4 as a “CYCLOTRON ROOM”) separated from a GMP (good manufacturing practice) room (identified in FIG.4 as a “GMP ROOM”), such as in a hospital or a laboratory setting.
  • CYCLOTRON ROOM a cyclotron room
  • GMP good manufacturing practice
  • the CYCLOTRON ROOM comprises the cyclotron 309, attached to the floor using hydraulic jacks 310, a controller 308 as can be associated with, integral with or in communication with a computer controller system or computer 315 or other suitable processor, the controller 308 and/or computer 315 having programming or software to control the operation and performance of the cyclotron 309 and to control operation and performance of the radiopharmaceutical micro- synthesis system 316 and/or the radiopharmaceutical macro- synthesis system 317; and, in communication with the cyclotron 309, a cyclotron chiller 302 to cool the cyclotron 309, and various gas lines 301, a water manifold 303, and gas valves 304 for gases and liquids used in operation of the cyclotron 309, the radiopharmaceutical micro-synthesis system 316 and/or the radiopharmaceutical macro-synthesis system 317.
  • the cyclotron 309 is fully self-shielded by a shielding system 312 that absorbs nearly all the ionizing radiation produced by the proton beam generated by the cyclotron 309.
  • the shield 312 around the cyclotron 309 which in some embodiments is less than 8 feet in diameter, facilitates reducing the radiation field around the cyclotron 309 to such a level that it is safe for a radiation worker to be present (typically ⁇ 1 mrem/hr) in the workspace around cyclotron 309 including the accelerator, such accelerator, for example, being illustrated in and described with reference to the cyclotron 100 of FIG. 2 and the cyclotron 200 of FIG. 3.
  • the shield 312 can be made, for example, from polymer/ceramic composite material, or other suitable material, to absorb nearly all ionizing radiation generated from the cyclotron 309.
  • the beam line or envelope of the cyclotron 309 can be directed to an external target 314, situated on the side of the cyclotron 309, for example.
  • the cyclotron 309, the radiopharmaceutical micro- synthesis system 316 and the radiopharmaceutical macrosynthesis system 317 are respectively configured to receive chemical reagents and/or one or more radioactive substances for radioisotope production, such as via conveyor belts or tubes 305, 306 and 307, or by other the suitable conveyances.
  • the radioisotope(s) travel(s) to a self-shielded chemical production module (CPM), such as to the radiopharmaceutical micro-synthesis system 316 situated next to the cyclotron 309 or travel to the radiopharmaceutical macro- synthesis system 317 inside a fully shielded GMP (good manufacturing practice) room (“GMP ROOM”) illustrated and identified in FIG 4 for a larger scale multi-dose radiochemical synthesis for transportation to outside labs and hospitals.
  • CPM self-shielded chemical production module
  • the CPM such as the radiopharmaceutical micro-synthesis system 316 situated within the CYCLOTRON ROOM and the radiopharmaceutical macro-synthesis system 317 in the GMP ROOM, holds reagents and solvents that are required during the radiopharmaceutical synthesis process.
  • the radiopharmaceutical solution is synthesized from the radioisotope and then purified for testing and administration.
  • a quality control can be performed of the radiopharmaceutical, which is readily apparent to those skilled in the art.
  • the computer 315 in conjunction with the controller 308 controls systems constituting or associated with the cyclotron 309, the radiopharmaceutical micro-synthesis system 316, the radiopharmaceutical macro-synthesis system 317 and/or a quality control system and ensures that these systems are capable of operating simultaneously, non-simultaneously and/or independently to ensure or facilitate the most efficient workflow.
  • the systems can be also configured to accept manual injection, input, or introduction of a radioisotope.
  • the computer 315, in conjunction with the controller 308, can also control multiple targets in the cyclotron, such as in the cyclotron 309, and move them into the beam of the cyclotron independently to produce different radioisotopes from different radioactive substances.
  • one or more of these systems of the biomarker generator system or cyclotron system 300 can be configured in conjunction with a vacuum pump to optimize the synthesis process and the yield of the radiopharmaceutical.
  • the controller 308 in conjunction with the computer or computer controller system 315 is used to control the beam of charged particles, such as a proton beam, and the beam intensity to accurately and precisely deliver the charged particles, such as protons or hydrogen ions, to the internal target radiochemical.
  • the computer controller system 315 in conjunction or association with the controller 308, desirably is a single control system for controlling the plurality of the components of the cyclotron system 300, such as the compact cyclotron 309 to provide the beam, such as a proton beam, of the requisite intensity, current and energy, and to control the radiopharmaceutical synthesis subsystem such as the radiopharmaceutical micro-synthesis system 316 and/or the radiopharmaceutical macro- synthesis system 317.
  • the computer controller system 315 in conjunction or association with the controller 308, controls all systems and ensures and facilitates operating all systems of the biomarker generator system or cyclotron system 300, namely the cyclotron, the synthesis system and the quality control system simultaneously, non-simultaneously and/or independently to ensure or facilitate the most efficient workflow.
  • the system can be also configured to accept manual injection, input, or introduction of a radioisotope, such as from the tube 307.
  • the computer 315, in conjunction or association with the controller 308, can also control multiple internal targets in the cyclotron and move them into the beam of the cyclotron independently to produce different radioisotopes.
  • the computer 315 in conjunction or association with the controller 308, can also control delivery of the beam, such as consisting essentially of protons, to an external target by directing the beamline to the external target 314.
  • the computer 315, in conjunction or association with the controller 308, can also control and automatically transfer via a conveyor belt or tube 371 the radioisotope produced into the radiopharmaceutical macrosynthesis system 317 for radiochemical/biomarker synthesis.
  • the automated radiopharmaceutical production for automatically producing a unit dose or multiple doses of the radiopharmaceutical includes a user interface integrated with the computer 315, the user interface enabling the selection of a selected radiopharmaceutical for production, the selection being made on and recorded by the user interface, whereby the user interface communicates an identity of the selected radiopharmaceutical to a computer.
  • a cyclotron such as the cyclotron 309, is in communication with the computer 315, which is in conjunction or association with the controller 308. The cyclotron produces a radioisotope associated with the selected radiopharmaceutical.
  • the cyclotron initiates production of the radioisotope upon receiving computer activating instructions; and upon receiving computer activating instructions, such as originating from the computer 315, the chemical production subsystem transfers, synthesizes, and purifies the radioisotope into a maximum quantity of a radiopharmaceutical on the order of up to ten units or higher doses using a disposable microfluidic radiopharmaceutical synthesis card system, for example.
  • the radiochemical synthesis subsystem(s) is/are integrated with or in communication with the cyclotron, which subsystem(s) are desirably fully automated.
  • the cyclotron 309 is desirably configured to be in communication with or integrated with the radiopharmaceutical micro-synthesis system 316, and the cyclotron 309 is desirably configured to be in communication with or integrated with the radiopharmaceutical macro-synthesis system 317.
  • the radiochemical synthesis subsystem(s), such as the radiopharmaceutical microsynthesis system 316 and the radiopharmaceutical macro-synthesis system 317 include one or more of a microreactor or a microfluidic chip for synthesizing one or more radiochemicals from one or more radioactive substances.
  • the radiochemical transfer to the chemistry modules 316 and 317, the radiopharmaceutical micro-synthesis system 316 and the radiopharmaceutical macro-synthesis system 317, for isolation and separation are automated and fully shielded. While the small-scale chemical synthesis in the chemistry module 316 can be conducted next to the cyclotron 309, the large-scale chemistry in the chemistry module 317 can be conducted in the adjoining separate GMP ROOM.
  • the radiochemical synthesis system is typically a simple “push button” synthesis system for generating FDG-F18 and NH3-13N radio-chemicals, for example, on an as needed basis in the hospital or clinic setting.
  • the improved biomarker generator allows dual operation using a liquid volume or solid sample of the target radioactive substance that is unusually small in the area of radiopharmaceutical production.
  • the radioisotope and at least one reagent are transferred to the radiochemical synthesis system, which is desirably fully automated using a computer user interface.
  • the radioisotope undergoes processing as necessary.
  • the radiopharmaceutical micro-synthesis system combines the radioisotope with the reagent or reagents to synthesize the biomarker.
  • Table 1 illustrates the nuclide production for a cyclotron system using different nuclides with varying beam conditions, run length and the resulting production yield using embodiments of the inventive cyclotron systems and methods according to the present invention.
  • the exemplary cyclotron is capable of producing the following radionuclides listed in Table 1. It should be noted that the Ga-68 production energy maximum is 12 MeV.
  • embodiments of the inventive cyclotron system of the present invention can produce a yield of F- 18 greater than 20 times with a beam current of about 15 micro- Amperes as compared with a conventional prior art cyclotron, such as that illustrated in FIG. 1.
  • the inventive cyclotron of the present invention can accelerate the protons at higher energies of up to 11 MeV, or even up to 15 MeV, and increased proton beam current capabilities up to 100 micro- Amperes, which is capable of producing single or multiple batches of biomarkers including 18 FDG, Na 18 F, 18 F-MISO, 18 FLT, 18 F-Choline, 18 F-DOPA and 18 F-PSMA as well as N-13 ammonia, C-l l labelled compounds, Cu64 as well as Ga68 compounds “on demand” even in a small hospital or medical clinic setting.
  • Embodiments of the inventive cyclotron can be configured to irradiate multiple internal and external targets and produce radiochemical at a much higher yield than that of previous prior art or conventional cyclotron systems.
  • novel design of the multiple targets including the use of amplifier systems of embodiments of this inventive compact cyclotron system allows for the production of higher proton beam current than the prior art cyclotrons thereby enabling the production of a variety of radioisotopes and radiochemicals in a single dose or multi-doses simultaneously by a simple push button interface on a computer, for example.
  • Table 2 illustrates the Technetium (Tc99m) production capabilities using embodiments of the inventive cyclotron of the present invention.
  • embodiments of the inventive cyclotron are capable of producing Technetium (Tc99m) at higher yields by increasing the energy and the beam energy and current.
  • Technetium (Tc-99m) is an isotope highly desired in a number of medical diagnostic imaging scans, such as Tc99m is used as a radioactive tracer for nuclear medicine such as using SPECT/CT (single photon emission computed tomography/computed tomography).
  • SPECT/CT single photon emission computed tomography/computed tomography
  • embodiments of the inventive cyclotron are versatile in producing several radioisotopes simultaneously for imaging, and believed to be advantageous over various prior art cyclotrons.
  • the inventive cyclotron can be modified to produce higher proton beam energies up to 15 MeV for producing higher quantities of Technetium (Tc-99m), for example.
  • a biomarker generator system 400 allows for the nearly on-demand and automated production of approximately one (1) unit dose or multiple unit doses of the biomarker via the schematic illustration depicted in FIG. 5.
  • a micro- accelerator cyclotron 401 produces a beam of charged particles that bombards target substances to create a precursory unit or multiple doses of a radioisotope 402.
  • the radioisotope is transferred to the radiopharmaceutical synthesis system 404 within the cyclotron room or is transferred to a large scale radiopharmaceutical synthesis system in a GMP room 405, which is an automated chemical module, where it is mixed with reagents 403 to create either a small dose 407 such as a unit dose or large multi doses 406 of the biomarker depending upon the need of the clinic or hospital.
  • a small dose 407 such as a unit dose or large multi doses 406 of the biomarker depending upon the need of the clinic or hospital.
  • embodiments of the inventive biomarker generator system allows for the nearly on-demand production of approximately one unit dose or multiple unit doses of biomarker via the schematic illustration 500 depicted.
  • the method of generating a unit dose or multi-doses of biomarker comprises several steps.
  • a compact cyclotron 501 is provided which generates charged particles in a vacuum 502.
  • the charged particles are accelerated along a path forming a beam envelope of charged particles 503.
  • the ion beam of charged particles is used to bombard a plurality of targets positioned within or outside of the cyclotron, the targets can be solid, or can also be in a liquid or a gaseous state, with the beam thereby producing a radioisotope that is transformed into a radioisotope-containing solution having an activity of less than, or equal to, approximately sixty (60) mCi 504.
  • the radioisotope-containing solution is transferred to a micro-reaction (or microfluidic) subsystem 505. Other chemical reagents may be added to this solution.
  • the radioisotope is concentrated yielding a concentrated radioisotope-containing solution 506 which can be used to synthesize approximately one unit dose or multiple unit doses of PET biomarker using the concentrated radioisotope-containing solution 507.
  • the entire process is desirably computer controlled and is typically fully automated.
  • the embodiments of the inventive cyclotron system are capable of selecting the type of radiochemical production typically by a simple “push-button” user interface to select either FDG-F-18 or NH2-N13 production, for example, on an as needed basis.
  • the micro-accelerator and the radiochemical synthesis subsystem with the regents together in the same system, enable the generation of a unit dose or multiple unit doses of the radioisotope in combination with the synthesis of a unit dose or unit doses of the biomarker.
  • Microreactors and microfluidic chips typically perform their respective functions in less than fifteen (15) minutes, some in less than two (2) minutes.
  • a radiochemical synthesis subsystem having at least one microreactor and/or microfluidic chip is flexible and may be used to synthesize a biomarker other than FDG-F18, including a biomarker that is labeled with a radioisotope other than fluorine- 18, such as carbon-11, nitrogen- 13, or oxygen- 15, Cu 64 etc.
  • a subsystem may comprise parallel circuits, enabling simultaneous production of a unit dose or multiple unit doses of a variety of biomarkers.
  • the half-lives of the radioisotopes (and, hence, the biomarkers) most suitable for safe molecular imaging of a living organism are limited, e.g., the half-life of fluorine- 18 is 110 minutes, nearly “on-demand” production of multiple doses of biomarkers presents a significant advancement for both clinical medicine and biomedical research.
  • the present invention aims to provide larger amounts of 18F radioisotope that could lead to multiple doses of [18F] FDG “on-demand” with greater efficiency, for example, which is viable even for small hospitals and clinics as compared with various prior art systems.
  • Embodiments of the inventive compact biomarker generator cyclotron system can also produce other positron emitting isotopes, such as F-18, C-l l, N-13, 0-15, Cu-64, Ga- 67, In-111, 1-123, Ac-225, Pd-103 and Ga-68, depending on various industrial and biomedical research applications.
  • Embodiments of the inventive compact cyclotron system are advantageously compact as they can be typically installed in a spacing of 5 meters by 5 meters, can be self-shielded and can be placed in any spacing near an imaging device such as the PET/CT table.
  • embodiments of the inventive compact cyclotron system are relatively easy to maintain, and are relatively cost effective, thereby making medical isotope and biomarker generating of a single dose or multiple doses “on-demand” useful for a variety of applications even for in house biomarker generation and for small regional hospitals.
  • embodiments of the inventive compact biomarker generator cyclotron system can generate radio-chemically pure, clinical grade radiotracers and radiopharmaceuticals ready for use in humans, animals and other mammals “on-demand” and for in vitro and in vivo biomedical research applications.
  • the inventive cyclotron system is desirably fully automated for radiochemistry and for quality control testing evaluation.
  • the relative reduced cost and relative reduced infrastructure requirements of the compact micro-accelerator compared to various known cyclotrons, coupled with the built-in automated radio-chemistry synthesis subsystem having at least one or more of a microreactor and/or a microfluidic chip facilitates making in house biomarker generation a viable, efficient option for small clinics and hospitals Moreover, embodiments of the inventive cyclotron system can be advantageous for nuclear cardiology/oncology applications, for example.

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Abstract

L'appareil et les procédés de production de produit radiochimique comprennent un cyclotron pour générer un faisceau de particules chargées possédant une enveloppe de faisceau constituée essentiellement de particules dotées d'une énergie dans la plage de 7 MeV à 11 MeV ; un accélérateur pour diriger le faisceau de particules chargées le long d'un trajet ; une pluralité de cibles positionnée à l'intérieur ou à l'extérieur du cyclotron, la pluralité de cibles étant positionnée dans le trajet du faisceau de particules chargées, les cibles comprenant une substance cible possédant une composition sélectionnée pour produire une substance radioactive pendant l'interaction avec le faisceau de particules chargées, la substance cible se trouvant dans un état solide, gazeux ou liquide ; un sous-système de synthèse radiochimique intégré au cyclotron, le sous-système de synthèse radiochimique possédant un ou plusieurs éléments parmi un microréacteur ou une puce microfluidique, le sous-système de synthèse radiochimique étant configuré pour recevoir la substance radioactive, pour recevoir au moins un réactif pour synthétiser le produit radiochimique.
PCT/US2024/031964 2023-06-08 2024-05-31 Cyclotron compact 7 mev à 11 mev à des fins de production d'isotopes médicaux Ceased WO2024253964A2 (fr)

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