EP1287532A2

EP1287532A2 - Method for producing ?18 f]fluoride ion

Info

Publication number: EP1287532A2
Application number: EP01941492A
Authority: EP
Inventors: Jorge R. Barrio; Nagichettiar Satyamurthy; Michael E. Phelps
Original assignee: University of California; University of California Berkeley; University of California San Diego UCSD
Current assignee: University of California; University of California Berkeley; University of California San Diego UCSD
Priority date: 2000-05-17
Filing date: 2001-05-16
Publication date: 2003-03-05
Also published as: WO2001087235A2; JP2003536055A; EP1287532A4; WO2001087235A3; AU2001274843A1

Abstract

A method for producing [18F] fluoride ion comprises loading an enclosed chamber (16) of a metal target with [18O]oxygen gas. The [18O] oxygen gas is irradiated in the enclosed chamber (16) to produce [18F] fluoride ion in the chamber (16). The produced[18F]fluoride ion is removed from the chamber (16) without opening the target, preferably by introducing a solubilizing agent into the enclosed chamber (16) to solubilize produced [18F] ion from the enclosed chamber (16) without opening the target. The remaining [18O]oxygen gas is removed from the chamber (16) for reuse prior to removing the [18F]fluoride ion from the chamber (16). The produced [18F]fluoride ion is reactive and can be used to produce radiolabeled compounds such as 2-deoxy-2[18F]fluoro-D-glucose.

Description

METHOD FOR PRODUCING [¹⁸F]FLUORIDE ION

Cross-Reference to Related Application

This application claims priority of U.S. Provisional Patent Application entitled PRODUCTION OF [¹⁸F]FLUORIDE ION, filed May 17, 2000, the entire disclosure of which is incorporated herein by reference.

Field of the Invention

The present invention is directed to methods for producing [' ⁸F] fluoride ion, and more particularly, methods for producing [¹⁸F] fluoride ion using [¹⁸O]oxygen gas.

Acknowledgment of Government Support

This invention was made with government support under Contract No. DE-FC03- 87-ER60615, awarded by the Department of Energy. The Government has certain rights in this invention.

Background

Positron emission tomography (PET) is a unique diagnostic imaging modality that measures the time-dependent localized concentrations of radiopharmaceuticals labeled with position-emitting radionuclides within the human body. Fluorine- 18 is used in the preparation of radiopharmaceuticals, such as 2-deoxy-2[¹⁸F]fluoro-D-glucose (FDG), for PET imaging determinations. Fluorine- 18 labeled fluoride ion has found widespread use in the synthesis of FDG for clinical use, but it is also used to produce a wide variety of other PET biological probes for research and clinical investigations of the brain, heart, and in the diagnosis of cancer.

Today there are more than 100 cyclotron facilities world- wide that produce [¹⁸F]fluoride ion for use in the preparation of radiopharmaceuticals. The development of a more reliable, higher yield, and more economical method for the cyclotron-produced fluorine- 18 radionuclide in the form of [¹⁸F]fluoride ion would be highly beneficial. Fluorine- 18 is commonly produced by proton irradiation of the stable oxygen- 18 isotope according to the ¹⁸O(p,n)¹⁸ F nuclear reaction. There are two chemical forms of cyclotron-produced fluorine- 18 labeled precursors used for the synthesis of ¹⁸F-labeled radiopharmaceuticals for research and clinical PET imaging, namely, [¹⁸F]fluoride ion and [¹⁸F]fluorine gas. Fluoride ion is generally used in nucleophilic substitution reactions, and fluorine gas is used in electrophilic reactions. [¹⁸F]fluoride ion is typically produced using liquid [¹⁸O]water as the target material, and [¹⁸F] fluorine gas is typically produced using [¹⁸O]oxygen.

More specifically, the standard method for the cyclotron production of aqueous [¹⁸F]fluoride ion is by irradiation of [¹⁸O]water using low-energy (10-17 MeN) protons according to the nuclear reaction ¹⁸O(p,n)¹⁸F. (See Ruth, TJ. and Wolf, A.P. (1979), Absolute cross sections of the production of ¹⁸F via the ¹⁸O(p,n)¹⁸F reaction. Radiochim. Ada 26, 21-24.) This reaction, which uses the stable isotope oxygen-18 as the target material, offers a significantly higher yield than older deuterons-on-neon methods, giving about 188 mCi/μA yield at saturation for 11 MeN protons. The typical [¹⁸O] water target holds about 0.35 to 1.2 mL of water, and using 20-30 μA beam current will easily yield cure-levels of [¹⁸F] fluoride ion for a 60-120 minute bombardment. However, this method suffers several drawbacks, including (I) the cost of the [¹⁸O] ater (currently about $175/gram for 97% enriched, and $234/gram for 99% enriched), (ii) the limited availability of [¹⁸O]water and the dependence of PET centers on foreign sources for the supply of this critical raw material, and (iii) target reliability and yield issues. After a bombardment, the [¹⁸O]water is either separated from the [¹⁸F] fluoride ion using a small trap-and-release anion exchange column with the recovered [¹⁸O] water, containing metallic cations, being collected and saved, or is simply evaporated and lost as the first step in the radiochemical labeling process. Wliile some production facilities are currently reusing their recovered [¹⁸O]water, the upcoming FDA regulations for PET radiopharmaceuticals mandated by the Food and Drug Modernization Act (FDAMA 1997) will require purification and recertification of the [^!8O]water as a manufacturing component of the drug product after a production run. Gas targets that use [¹⁸O]oxygen gas as the target material were developed in the 1980's and 1990's, primarily as a means to produce electrophilic [¹⁸F]fluorine gas. This production can be accomplished either by using pure [¹⁸O]oxygen gas or by using a mixture of [¹⁸O]oxygen gas and stable fluorine. If pure [¹⁸O]oxygen gas is used, stable fluorine gas is added to the target in a second bombardment step. With either method, the key to removal of the ¹⁸F-activity is the exchange of the [¹⁸F] fluorine atoms on the walls of the metal target with the carrier fluorine, allowing most of the activity to be released as molecular [¹⁸F]fluorine along with the carrier fluorine gas. With this method, the ¹⁸F-activity cannot be delivered from the metal target unless it is exchanged with stable fluorine. As a result, high specific activity radiopharmaceuticals cannot be prepared from electrophilic [¹⁸F]fluorine gas.

The production and release of [^{! 8}F]fluoride ion prepared by proton bombardment of [¹⁸O]oxygen gas was reported by Nickles et al. (Nickles, R.J. et al. (1983) An ¹⁸O₂ target for the high yield production of ¹⁸F-fluoride. Int. J. Appl. Radial Isot. 34, 625-629, the disclosure of which is incorporated herein by reference.) In this work, a high- pressure gas target, designed to be used with a 10-MeN proton beam from a tandem Nan de Graaff linear accelerator, was fitted with a silver-coated 10 mL Pyrex glass text tube inserted inside the target. The silver on the tube reacted with the [¹⁸F] fluorine produced during bombardment. After irradiation of [¹⁸O] oxygen gas, the glass liner, with the ¹⁸F- activity adhered to the walls, was manually removed from the target and about 70-80% of the activity was rinsed off the glass tube using hot water. The recovered aqueous [¹⁸F]fluoride ion was then used in the nucleophilic fluorination of methyl iodide in the presence of silver oxide to give [¹⁸F]fluoromethane. During the past 16 years no further use of this method has been reported. This method has the significant disadvantage that the manual removal of the [¹⁸F]fluoride ion exposes the user to radiation.

It would be desirable to have a method that provides (i) remote, automated recovery of [¹⁸F]fluoride ion; (ii) easy release of [¹⁸F]fluoride ion from the metal target surface; and (iii) reactive [¹⁸F]fluoride ion for the synthesis of large amounts of ^I8F- labeled radiopharmaceuticals. Summary of the Invention

In one embodiment, the present invention is directed to a method for producing [^I8F]fluoride ionfrom [¹⁸O]oxygen gas that attempts to address the drawbacks of the prior art. In one embodiment, the method comprises first loading an enclosed chamber of a metal target with [¹⁸O]oxygen gas. The [¹⁸O]oxygen gas in the chamber of the metal target is irradiated to produce [¹⁸F]fluoride ion in the chamber. The produced [¹⁸F] fluoride ion is removed from the chamber without opening the target. The invention provides remote, automated recovery of reactive [^{! 8}F]fluoride ion with easy release of the [¹⁸F]fluoride ion from the metal target surface. The thereby recovered [^lsF]fluoride ion can be used in the synthesis of [¹⁸F]labeled radiopharmaceuticals, typically by nucleophilic displacement using appropriate precursor substrates, and other radiolabeled compounds.

In another embodiment, the invention is directed to a method for producing [¹⁸F]fluoride ion. The method comprises loading an enclosed chamber of a metal target with [¹⁸O]oxygen gas. The [¹⁸O]oxygen gas is irradiated in the enclosed chamber to produce [¹⁸F]fluoride ion in the chamber. A solubilizing agent is introduced into the enclosed chamber, without opening the target, to solubilize produced [¹⁸F]fluoride ion. The solubilizing agent and produced [¹⁸F]fluoride ion are removed from the enclosed chamber without opening the target. The method of the invention offers several important advantages over the use of liquid [' ⁸O] water. First, gas targets are able to withstand relatively higher beam currents than small-volume [^l8O] water targets, which translates to higher product yields and more reliable operation. Second, the [¹⁸O]oxygen gas target material can also be efficiently recovered after the bombardment and can be recycled for subsequent runs. Further, the methods of the invention are superior to the method disclosed by Nickles et al. in that the present methods provide remote, automated recovery of the [¹⁸F]fiuoride ion, thereby minimizing contact with radioactivity.

The methods of the invention benefit PET. Specifically, clinical radiopharmaceuticals such as FDG can be produced in higher yields, which means extended availability for patients at lower cost. Further, the inventive methods make available to distribution centers low-cost [¹⁸F] fluoride ion, which is an important tool that will make available to molecular biology researchers a large number of biological probes, such as 3'-deoxy-3'[^I8F]fluorothymidine (FLT) for tumor proliferation, 9-(4- [¹⁸F]fluoro-3-hydroxymethyl-butyl)guanine ([¹⁸F]fluoropeniciclovir, FHBG) for gene expression, and a variety of compounds for receptor imaging and other investigations.

Description of the Drawings

Embodiments of the invention will now be described with reference to the following drawings wherein: FIG. 1 is a side cross-sectional view of a metal target for use in connection with the present invention; and

FIG. 2 is an end view of the metal target of FIG. 1. °

Detailed Description

The present invention is directed to methods for producing [^{l 8}F]fluoride ion from [¹⁸O]oxygen gas in a metal target.

A suitable metal target for use in connection with the present invention is depicted in FIGs. 1 and 2. The metal target has a generally cylindrical sidewall 10, a proximal end wall 12, and a distal end wall 14, which together form a chamber 16. The chamber 16 is preferably conical-shaped (10 mm diameter entrance tapering to 15 mm at the back) with a 15 mL volume. The chamber 16 has an inner wall 18 made of a suitable metal, i.e., a metal from which [¹⁸F]fluoride ion can be removed. Examples of suitable metals for use in connection with the invention include, but are not limited to, nickel, silver, copper, gold, tantalum, stainless steel, titanium, and alloys thereof, as well as one of these metals plated with another of these metals, e.g., gold-plated copper. Particularly preferred target materials include high purity electroform nickel and nickel- 200. The proximal end wall 12 of the target is connected to a suitable cyclotron (not shown). A preferred cyclotron for use in connection with the present invention is an RDS-112 negative ion cyclotron, commercially available from CTI.

[¹⁸O]oxygen gas is loaded in the enclosed chamber 16 through an oxygen valve 20 to a suitable pressure. For example, when the chamber 16 has a 15 mL volume, the [^I8O]oxygen gas is loaded to a pressure of about 200 to about 220 psi. The [¹⁸O]oxygen gas is irradiated with high energy protons from the cyclotron. The protons preferably have an energy greater than 5 MeN, preferably from about 5 to about 16 MeN. The protons pass from the cyclotron through a passage 21 in the proximal end wall 12 at about 10 to about 60 μA for a time period ranging from about 10 minutes to about 2 hours to produce [¹⁸F]fluoride ion on the walls of the chamber. Thereafter, the [¹⁸O]oxygen gas is removed from the chamber 16 through the oxygen valve 20 and cryorecovered for subsequent reuse.

During the irradiation, the cyclotron is kept under high vacuum, while the chamber 16 is maintained at a pressure. An aluminum vacuum foil 22 and a havar target foil 24 are provided within the passage 21 between the cyclotron and the chamber 16 to maintain the pressure differential . To counteract the heat of the nuclear reaction and keep the foils 22 and 24 cool, an inert gas, such as helium, neon, nitrogen or argon, is passed through a cooling passage 25 that runs between the foils. The irradiation also generates a significant amount of heat in the chamber 16 due to the protons being passed through the metal target. A water cooling jacket 26 is provided within the sidewall 10 to maintain the chamber at a temperature ranging from about 12°C to about 17°C, with 12° to 15 °C water being passed through the jacket.

After removal of the [¹⁸O]oxygen gas, a suitable liquid solubilizing agent is introduced into the enclosed chamber of the metal target for removal of the [^,8F]fluoride ion. Suitable solubilizing agents for use in connection with the present invention include water, aqueous salt solutions, organic solvents, organic acids and their solutions in water or an organic solvent, and combinations thereof. Examples of suitable aqueous salt solutions include ΝaOH, Νa₂CO₃, NaHCO₃, sodium oxalate, sodium acetate, sodium propionate, sodium butyrate, sodium succinate, sodium benzoate, sodium tatrate, sodium lactate; KOH, K₂CO₃, KHCO₃, potassium oxalate, potassium acetate, potassium propionate, potassium butyrate, potassium succinate, potassium benzoate, potassium tartrate, potassium lactate; RbOH, Rb₂CO₃, RbHCO₃, rubidium oxalate, rubidium acetate, rubidium propionate, rubidium butyrate, rubidium succinate, rubidium benzoate, rubidium tartrate, rubidium lactate; CsOH, Cs₂CO₃, CsHCO₃, cesium oxalate, cesium acetate, cesium propionate, cesium butyrate, cesium succinate, cesium benzoate, cesium tartrate, cesium lactate; NH₄OH, (NH₄)₂CO₃, NH₄HCO₃, ammonium oxalate, ammonium acetate, ammonium propionate, ammonium butyrate, ammonium succinate, ammonium benzoate, ammonium tartrate, ammonium lactate; tetraalkyl, trialkylalkylaryl, and dialkyldialkylaryl ammonium salts with the following anions: hydroxide, carbonate, bicarbonate, acetate, oxalate, propionate, tartrate, lactate, succinate, benzoate; divalent cations such as calcium, barium, strontium with anionic groups such as hydroxide and acetate; sodium, ammonium, potassium salts of ethylenediamine tetraacetic acid; and combinations thereof. Examples of suitable organic solvents include lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t-butanol; aromatic compounds such as benzyl alcohol, phenol, cresols; ethers such as tetrahydrofuran, dioxane; acetonitrile; dimethylformamide; dimethylsulfoxide; trifluoroethanol; hexafluoroisopropanol; hexamethylphosphorictriamide; pyridine; chloroform; and combinations thereof. Examples of suitable organic acids include acetic acid, propionic acid, oxalic acid, succinic acid, butyric acid, valeric acid, tartaric acid, lactic acid, benzoic acid ethylenediamine tetraacetic acid and combinations thereof.

During removal of the [^I8F] fluoride ion, the metal target is closed so that the chamber 16 remains enclosed to prevent the user from contact with radioactivity. The solubilizing agent is introduced into the enclosed chamber of the metal target through a liquid fill port 28 without opening the target. The solubilizing agent is allowed to remain in the chamber 16 for a time sufficient to remove most of the [¹⁸F]fluoride ion from the metal target, preferably for a period of time ranging from about 10 seconds to about 10 minutes. The temperature of the chamber should be kept below the boiling point of the solubilizing agent, and preferably maintained at a temperature ranging from about 4°C to about 100°, more preferably from about 25 °C to about 100°C.

The solubilizing agent is removed from the enclosed chamber through a liquid recovery port 30 by, for example, pressurizing the chamber with an inert gas, such as helium, argon, neon, or nitrogen. The gas is introduced into the chamber 16 through a gas port 32 and removed from the chamber through the liquid recovery port 30. With this design, the user does not come into contact with radioactivity when removing the [^,8F] fluoride ion from the chamber 16. Thereafter, the solubilizing agent is passed through a suitable exchange resin cartridge, preferably an anion exchange resin cartridge, to trap the [¹⁸F]fluoride ion thereon. The [¹⁸F]fluoride ion is eluted off the resin cartridge with a suitable eluting agent. Particularly preferred eluting agents include inorganic and organic salt solutions, such as potassium carbonate, potassium oxalate, potassium hydroxide, potassium bicarbonate, tetraalkylammonium bicarbonate (preferably lower alkyl, such as methyl, ethyl, propyl or butyl), tetraalkylammonium carbonate, tetraalkylammonium hydroxide, and combinations thereof.

Other methods for isolating the [¹⁸F]fluoride ion can also be used. For example, the solubilizing agent can be evaporated to isolate the [¹⁸F]fluoride ion. After the solubilizing agent and [¹⁸F]fluoride ion are removed from the target, the target is cleaned for use. A preferred method for cleaning the target involves flushing with water followed by an organic solvent, such as methanol, through the chamber 16. The water and solvent are introduced into and removed from the chamber 16 through the liquid fill port 28 and liquid recovery port 30, respectively. To completely remove the solvent from the chamber 16, the chamber is heated to about 100°C with heaters 34 within the sidewall 10, and an inert gas, such as helium, argon, neon or nitrogen, is passed through the chamber 16. The inert gas is introduced through the gas port 32 and removed through the liquid recovery port 30.

If desired, an insert can be placed into the chamber so that the [¹⁸F]fluoride ion deposits onto the insert. For example, the insert can be made of treated glass (e.g., glass plated with silver or another metal), such as is described in aforementioned Nickles et al. reference, or the insert can be made of a suitable metal, such as those set forth above. However, even if an insert is used, in accordance with the invention, the [¹⁸F] fluoride ion is removed from the chamber while the target is closed. The methods of the present invention can be used to produce reactive

[¹⁸F]fluoride ion for use in the production of a number of radiolabeled compounds, including 2 -deoxy-2 [ ^{I 8}F] fluoro -D -glucose(FDG) , 2 -( l - { 6 - [2 - [¹⁸F]fluoroethyl(methyl)amino]-2-naphthyl}) ethylidenemalono-nitrile (¹⁸F-FDDNP), 2'- [¹⁸F]fluoroethylspiperone(¹⁸F-FESP), 3'-deoxy-3'-[¹⁸F]fluorothymidine(¹⁸F-FLT), 9-[(3- [¹⁸F]fluoro-l-hydroxy-2-propoxy)methyl]guanine ([¹⁸F]FHPG), 9-(4-[¹⁸F]fluoro-3- hydroxymethylbutyl)guanine ([¹⁸F]FHBG), [¹⁸F]fluorobromomethane, [¹⁸F]fluoroiodomethane, [¹⁸F]fluorotosyloxy-methane and their higher homologs, and 6- [¹⁸F]fluoro-L-dopa and related fluoroamino acids using nucleophilic synthetic procedures. As used herein, the term "reactive [¹⁸F]fluoride ion" means that the [¹⁸F]fluoride ion is capable of being reacted with suitable reagents to produce FDG in accordance with the following method:

A small anion exchange cartridge (such as an Accell QMA Plus, commercially available from Waters Associates and activated with 1.0 M potassium bicarbonate solution) is used to trap the [^I8F] -fluoride ion released from the target. The [^I8F] -fluoride ion is eluted off the cartridge with 0.4 mL of K₂CO₃ solution (0.04 M), and Kryptofix 222 (10-20 mg) is added. The aqueous solution is evaporated at 115 °C with a stream of dry nitrogen, and further moisture is removed by azeotropic distillation with acetonitrile (3 x 1 mL). A solution of l,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D- mannopyranose (10-25 mg) in acetonitrile (1.0-2.0 mL) is added to the dry K¹⁸F/Kryptofix complex, and the reaction mixture is heated for 5 to 15 minutes at 85 °C. The fluorinated product solution is passed through a Classic silica Sep-Pak cartridge (commercially available from Waters Associates, Milford, MA) and eluted with ether (5 to 15 mL). The eluent is evaporated with a stream of nitrogen in a glass vessel kept at 100° to 115°C. One mL of 1.0 N hydrochloric acid is added to the residue and heated at 115 °C for 10 to 15 min. The hydrolyzed mixture is then transferred onto the top of a column of ion-retardation resin (Bio-Rad, AG11 A8, 50-100 mesh) pre-equilibrated with sterile water. The hydrolysis vessel is rinsed with water (10-20 mL) onto the column, and the FDG that is eluted from the column is passed through tandem Classic alumina and C-18 Sep-Pak cartridges (available from Waters Associates) which have been washed with absolute ethanol (5 to 10 mL) followed by sterile water (10 to 20 mL). The resulting solution is sterilized by passing through a Millipore filter (0.22 μM) into a sterile 30 mL multi-injection vial containing appropriate amounts of sodium chloride to make the final solution isotonic. The activity of the FDG is measured using a dose calibrator (such as a CRC-3512 commercially available from Capintec Inc.) and corrected to the end of bombardment (EOB). This activity is compared to the activity of ¹⁸F-fluoride released from the target (corrected to EOB) to determine the yield of FDG produced. Accordingly, the term "5% reactive" indicates that the [^I8F]fluoride ion can be converted to FDG in a 5% yield, the term "10% reactive" indicates that the [¹⁸F]fluoride ion can be converted to FDG in a 10% yield, the term "20% reactive" indicates that the [¹⁸F] fluoride ion can be converted to FDG in a 20% yield, etc. Preferably the [¹⁸F]fluoride ion produced in accordance with the inventive methods is at least about 5% reactive, more preferably at least about 10% reactive, even more preferably at least about 20% reactive, still more preferably at least about 30% reactive, yet more preferably at least about 50% reactive, even more preferably at least about 70% reactive, as shown in Tables I and II of the Examples below.

EXAMPLES Example 1 Preparation of [^,SF] fluoride ion

A 15 mL volume, conical-shaped (10 mm diameter entrance tapering to 15 mm at the back) metal target was provided. The metal used for each target is set forth in Table I. [¹⁸O]oxygen gas was loaded in the target to a pressure of about 210 to 215 psi and irradiated with 11 MeN protons at 40 μA for 1 hour with an RDS- 112 cyclotron. The [¹⁸O]oxygen gas was then cryorecovered with an efficiency of >99% for subsequent reuse. The target was filled with 15 mL of water to solubilize [¹⁸F]fluoride ion from the walls of the target body. The water was passed through an anion exchange resin cartridge (Accell QMA Plus and activated with 1.0 M potassium bicarbonate solution) that trapped [¹⁸F]fluoride ion with an efficiency of about 90% to 98%. 90% to 91% of the [¹⁸F]fluoride ion was eluted off the resin cartridge with 0.4 mL of K₂CO₃ solution (0.04 M). Preparation of FDG

To the [¹⁸F]fluoride ion eluted from the cartridge, Kryptofϊx 222 (10-20 mg) was added. The aqueous solution was evaporated at 115 ° C with a stream of dry nitrogen and further moisture was removed by azeotropic distillation with acetonitrile (3 x 1 mL). A solution of 1 ,3 ,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose (10-25 mg) in acetonitrile (1.0-2.0 mL) was added to the dry K¹⁸F/Kryptofix complex, and the reaction mixture was heated for 5 to 15 minutes at 85 ° C . The fluorinated product solution was passed through a Classic silica Sep-Pak cartridge and eluted with ether (5 to 15 mL). The eluent was evaporated with a stream of nitrogen in a glass vessel kept at 100° to ll5°C. One mL of 1.0 N hydrochloric acid was added to the residue and heated at 115 °C for 10 to 15 min. The hydrolyzed mixture was then transferred onto the top of a column of ion-retardation resin (Bio-Rad, AG11A8, 50-100 mesh) pre-equilibrated with sterile water. The hydrolysis vessel was rinsed with water (10-20 mL) onto the column, and the FDG that was eluted from the column was passed through tandem Classic alumina and C-18 Sep-Pak cartridges (available from Waters Associates) which had been washed with absolute ethanol (5 to 10 mL) followed by sterile water (10 to 20 mL). The resulting solution was sterilized by passing through a Millipore filter (0.22 μM) into a sterile 30 mL multi-injection vial containing appropriate amounts of sodium chloride to make the final solution isotonic.

The yields of [¹⁸F]fluoride ion activity eluted from the target and percent yields of FDG produced from the eluted activity were determined (corrected to EOB) and are provided in Table I. Table I

* Corrected to EOB

Example 2

Preparation of [^,SF] fluoride ion

A 15 mL volume, conical-shaped (10 mm diameter entrance tapering to 15 mm at the back) metal target was provided. The metal used for each target is set forth in Table II. [¹⁸O]oxygen gas was loaded in the target to apressure of about 210 to 215 psi in and irradiated with 11 MeN protons at 40 μA for 1 hour with an RDS-112 cyclotron. The [¹⁸O]oxygen gas was then cryorecovered with an efficiency of >99% for subsequent reuse. The target was filled with 15 mL of a solubilizing agent as set forth in Table II to solubilize [¹⁸F]fluoride ion from the walls of the target body. The water was passed through an anion exchange resin cartridge (Accell QMA Plus and activated with 1.0 M potassium bicarbonate solution) that trapped [^I8F]fluoride with an efficiency of about 90% to 98%. 85% to 97% of the [¹⁸F]fluoride ion was eluted off the resin cartridge with 0.4 mL of K₂CO₃ solution (0.04 M). The [¹⁸F]fluoride ion was used to produce FDG as described in Example 1. The yields of [¹⁸F]fluoride ion activity eluted from the target and percent yields of FDG produced from the eluted activity were determined (corrected to EOB) and are provided in Table II. Table II

The preceding description has been presented with reference to presently preferred embodiments of the invention. Workers skilled in the art and technology to which this invention pertains will appreciate that alterations and changes in the described methods may be practiced without meaningfully departing from the principal, spirit and scope of this invention. Accordingly, the foregoing description should not be read as pertaining only to the precise methods described, but rather should be read consistent with and as support to the following claims which are to have their fullest and fair scope.

Claims

1. A method for producing [¹⁸F]fluoride ion comprising: loading an enclosed chamber of a metal target with [¹⁸O]oxygen gas; irradiating the [¹⁸O]oxygen gas in the enclosed chamber to produce [¹⁸F]fluoride ion in the chamber; and removing produced [' ⁸F] fluoride ion from the chamber without opening the target.

2. The method of claim 1 , further comprising removing[¹⁸O]oxygen gas from the chamber for reuse prior to removing the [¹⁸F]fluoride ion from the chamber.

3. The method of claim 1, wherein the metal is selected from the group consisting of nickel, silver, copper, gold, tantalum, stainless steel, titanium, and alloys thereof.

4. The method of claim 1 , wherein the produced [^I8F]fluoride ion is at least about 5% reactive.

5. The method of claim 1, wherein the produced [¹⁸F]fluoride ion is at least about 30%) reactive.

6. The method of claim 1 , wherein the produced [' ⁸F]fluoride ion is at least about 50% reactive.

7. The method of claim 1 , wherein the produced [¹⁸F]fluoride ion is at least about 70%) reactive.

8. A method for piOducing[¹⁸F]fluoride ion comprising: loading an enclosed chamber of a metal target with [^I8O]oxygen gas; irradiating the [¹⁸O]oxygen gas in the enclosed chamber to produce [¹⁸F]fluoride ion in the chamber; introducing a solubilizing agent into the enclosed chamber without opening the target to solublize produced [¹⁸F]fluoride ion; and removing the solubilizing agent and produced [^lsF]fluoride ion from the enclosed chamber without opening the target.

9. The method of claim 8, further comprising removing the remaining [^I8O] oxygen gas from the chamber for reuse prior to removing the [¹⁸F] fluoride ion from the chamber.

10. The method of claim 8, wherein the metal is selected from the group consisting of nickel, silver, copper, gold, tantalum, stainless steel, titanium, and alloys thereof.

11. The method of claim 8, wherein the metal is nickel.

12. The method of claim 8, wherein the metal is selected from the group consisting of electroplated nickel and nickel-200.

13. The method of claim 8, wherein the solubilizing agent is selected from the group consisting of water, aqueous salt solutions, organic solvents, organic acids and their solutions in water or an organic solvent, and combinations thereof.

14. The method of claim 8, wherein the solubilizing agent is water.

15. The method of claim 8, wherein the solubilizing agent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, s-butanol, t- butanol, benzyl alcohol, phenol, cresols, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide, trifluoroethanol, hexafluoroisopropanol, hexamethylphosphorictriamide, pyridine, chloroform, and combinations thereof.

16. The method of claim 8, wherein the [¹⁸O]oxygen gas is loaded to a pressure ranging from about 200 to about 220 psi.

17. The method of claim 8, wherein the inside the chamber is maintained at a temperature ranging from about 4 ° C to about 100 ° C during introduction and removal of the solubilizing agent.

18. The method of claim 8, wherein the produced [¹⁸F]fluoride ion is at least about 10% reactive.

19. The method of claim 8, wherein the produced [¹⁸F]fluoride ion is at least about 20% reactive.

20. The method of claim 8, wherein the produced [¹⁸F]fluoride ion is at least about 30%) reactive.

21. The method of claim 8, wherein the produced [¹⁸F]fluoride ion is at least about 50%) reactive.

22. The method of claim 8, wherein the produced [¹⁸F]fluoride ion is at least about 70%) reactive.

23. The method of claim 8, further comprising: passing the solubilizing agent and produced [' ⁸F] fluoride ion through an exchange resin cartridge to trap [¹⁸F]fluoride ion; and eluting [^I8F]fluoride ion off the resin cartridge with an eluting agent.

24. The method of claim 23, further comprising removing [^!8O]oxygen gas from the chamber for reuse prior to introducing the solubilizing agent into the chamber.

25. The method of claim 23, wherein the produced [¹⁸F]fluoride ion is at least about 30% reactive.

26. A method for producing a radiolabeled compound, comprising: producing [¹⁸F]fluoride ion in accordance with the method recited in claim 8; reacting at least a portion of the produced [¹⁸F]fluoride ion with at least one other compound to produce the radiolabeled compound.

27. The method according to claim 26, wherein the radiolabeled compound is selected from the group consisting of 2-deoxy-2[¹⁸F]fluoro-D-glucose, 3'-deoxy-3'- [ ^{1 8}F] fluorothymidine, 2 ' - [ ^{1 8}F] fluoroethylspiperone, 2-( l - { 6- [2- [¹⁸F]fluoiOethyl(methyl)amino]-2-naphthyl})ethylidenemalono-nitrile, 9-[(3-[¹⁸F]fluoro- 1 -hydroxy-2-propoxy)methyl] guanine, 9-(4- f¹⁸F]fluoro-3 -hydroxymethylbutyl)guanine, [¹⁸F]fluorobromomethane, [¹⁸F]fluoroiodomethane, [¹⁸F]fluorotosyloxy-methane, and 6- [ ^{] 8}F] fluoro-L-dopa.

28. The method according to claim 26, wherein the produced [¹⁸F]fluorideion is at least about 30% reactive.

29. The method according to claim 26, wherein the produced [¹⁸F]fluoride ion is at least about 50%) reactive.