Rapid isolation of cyclotron-produced gallium-68

Abstract

Methods for rapid isolation of radionuclides (e.g., .sup.68Ga) produced using a cyclotron and methods for recycling of the parent isotope (e.g., .sup.68Zn) are disclosed. In one version of the method, a solution including a radionuclide (e.g., .sup.68Ga) is created from a target including cations (e.g., .sup.68Zn). The solution including the radionuclide is passed through a first column including a sorbent comprising a hydroxamate resin to adsorb the radionuclide on the sorbent, and the radionuclide is eluted off the sorbent. The cations (e.g., .sup.68Zn) are recovered from a recovery solution that has passed through the first column by passing the recovery solution through a second column including a second sorbent comprising a cation exchange resin.

Claims

1. A method for producing a solution including a radionuclide, the method comprising: (a) bombarding a target solution with protons to produce a solution including a radionuclide, wherein the radionuclide is .sup.68Ga; (b) passing the solution including the radionuclide through a column including a sorbent to adsorb the radionuclide on the sorbent; and (c) eluting the radionuclide off the sorbent, wherein the sorbent comprises a hydroxamate resin, and wherein pH of the solution including the radionuclide before passing the solution including the radionuclide through the column is between 5 and 7.

2. The method of claim 1, wherein the target solution comprises .sup.68Zn-enriched zinc nitrate.

3. The method of claim 1, wherein step (c) comprises eluting the radionuclide off the sorbent using hydrochloric acid.

4. The method of claim 1, wherein step (c) comprises eluting the radionuclide off the sorbent with an amount of eluent of 5 milliliters or less, and wherein the method takes 30 minutes or less.

5. The method of claim 1, wherein step (b) comprises adjusting pH of the solution including the radionuclide before passing the solution including the radionuclide through the column.

6. The method of claim 5, wherein the adjusting of the pH comprises a dilution with water.

7. The method of claim 5, wherein the adjusting of the pH comprises an addition of a base, and wherein the base forms a soluble product with .sup.68Ga and .sup.68Zn.

8. The method of claim 1, wherein yield of the radionuclide from the solution including the radionuclide is greater than 80% by radioactivity.

9. The method of claim 1, wherein the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene, and wherein the hydroxamate resin has a particle size in a range of 10 to 100 microns.

10. The method of claim 1, wherein the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase.

11. A method for producing a solution including a radionuclide, the method comprising: (a) bombarding a solid target with protons to produce a solid radionuclide, wherein the radionuclide is .sup.68Ga; (b) creating a solution including the radionuclide from the solid radionuclide; (c) passing the solution including the radionuclide through a column including a sorbent to adsorb the radionuclide on the sorbent; and (d) eluting the radionuclide off the sorbent, wherein the sorbent comprises a hydroxamate resin, and wherein pH of the solution including the radionuclide before passing the solution including the radionuclide through the column is between 5 and 7.

12. The method of claim 11, wherein the solution comprises .sup.68Zn-enriched zinc nitrate.

13. The method of claim 11, wherein step (c) comprises eluting the radionuclide off the sorbent using hydrochloric acid.

14. The method of claim 11, wherein step (c) comprises eluting the radionuclide off the sorbent with an amount of eluent of 5 milliliters or less, and wherein the method takes 30 minutes or less.

15. The method of claim 11, wherein step (b) comprises adjusting pH of the solution including the radionuclide before passing the solution including the radionuclide through the column.

16. The method of claim 15, wherein the adjusting of the pH comprises a dilution.

17. The method of claim 15, wherein the adjusting of the pH comprises an addition of a base, and wherein the base forms a soluble product with .sup.68Ga and .sup.68Zn.

18. The method of claim 11, wherein yield of the radionuclide from the solution including the radionuclide is greater than 80%.

19. The method of claim 11, wherein the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene, and wherein the hydroxamate resin has a particle size in a range of 10 to 100 microns.

20. The method of claim 11, wherein the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a schematic of an automated system for the separation of .sup.68Ga radioisotope from a cyclotron produced solution including .sup.68Ga.

DETAILED DESCRIPTION OF THE INVENTION

(2) In one embodiment, the present disclosure provides a method for producing a solution including a radionuclide comprising the bombardment of a target solution with protons to produce a solution including a radionuclide, wherein the radionuclide is .sup.68Ga; the passing of the solution including the radionuclide through a column including a sorbent to adsorb the radionuclide on the sorbent; and the elution of the radionuclide off the sorbent, wherein the sorbent comprises a hydroxamate resin. In one form, the target solution may comprise .sup.68Zn-enriched zinc nitrate. The method may further comprise the elution of the radionuclide off the sorbent using hydrochloric acid, wherein an amount of eluent of 5 milliliters or less can be used. This method may take 30 minutes or less.

(3) The method may further comprise adjusting pH of the solution including the radionuclide before passing the solution including the radionuclide through the column. In one version, these adjustments of the pH may comprise a dilution of the solution with water. The volume of water for dilution may range from 10 to 50 milliliters. In another version, the adjusting of the pH may comprise an addition of an organic or inorganic base to the solution. In this other version, the base may form a water soluble product with .sup.68Ga and .sup.68Zn. In one form of this other version, the base is sodium bicarbonate. The pH of the solution including the radionuclide before passing the solution including the radionuclide through the column may be between 5 and 7, preferably in a range of 5.5 to 6.5.

(4) In this first embodiment, at least one of the steps of the method may be completed by an automated process using a remotely controlled radiochemistry module for processing in a hot cell as depicted in FIG. 1. The yield of the radionuclide from the solution including the radionuclide may be greater than 80% by radioactivity, or greater than 85% by radioactivity, or greater than 90% by radioactivity, or greater than 95% by radioactivity. In another form, the hydroxamate resin may comprise hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene. In one non-limiting form, the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase. The hydroxamate resin may have a particle size in a range of 10 to 100 microns, or in a range of 20 to 70 microns, or in a range of 30 to 60 microns. In one non-limiting form, the hydroxamate resin has a particle size in a range of 37 to 55 microns.

(5) In a second embodiment, the present disclosure provides a method for producing a solution including a radionuclide comprising the bombardment of a target solution including zinc cations with protons to produce a solution including a radionuclide; the passing of the solution including the radionuclide through a first column including a first sorbent to adsorb the radionuclide on the first sorbent; and the recovery of zinc cations from a recovery solution that has passed through the first column by passing the recovery solution through a second column including a second sorbent comprising a cation exchange resin. In one form, the method may comprise adjusting the pH of the recovery solution before passing the recovery solution through the second column. A beneficial pH range for the recovery solution before passing the recovery solution through the second column is a pH in a range of 3 to 7, or 4 to 6, or 4.5 to 5.5.

(6) The first sorbent may be a hydroxamate resin comprising hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene. In one non-limiting form, the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase. The hydroxamate resin may have a particle size in a range of 10 to 100 microns, or in a range of 20 to 70 microns, or in a range of 30 to 60 microns. In one non-limiting form, the hydroxamate resin has a particle size in a range of 37 to 55 microns. The second sorbent may comprise a polymeric resin having sulfonic acid groups. The second sorbent may be a polystyrene-divinylbenzene sulfonic acid such as that sold under the tradename AG® 50W-X8. The second sorbent may be a styrene-divinylbenzene co-polymer containing iminodiacetic acid groups such as that sold under the tradename Chelex® 100.

(7) The method may further comprise washing the second column with deionized water before passing the recovery solution through the second column. The method may also comprise pushing air through the second column before passing the recovery solution through the second column. In yet another form, the target solution may comprise .sup.68Zn-enriched zinc nitrate. The recovery of the zinc cations from the second column may be 90% or greater based on weight of the zinc cations in the target solution, or 93% or greater based on weight of the zinc cations in the target solution, or 95% or greater based on weight of the zinc cations in the target solution, or 98% or greater based on weight of the zinc cations in the target solution. In this second embodiment, at least one of the steps of the method may be completed by an automated process.

(8) In a third embodiment, the present disclosure provides a method for producing a solution including a radionuclide comprising the bombardment of a solid target with protons to produce a solid radionuclide, wherein the radionuclide is .sup.68Ga; the creation of a solution including the radionuclide from the solid radionuclide; the passing of the solution including the radionuclide through a column including a sorbent to adsorb the radionuclide on the sorbent; and the elution of the radionuclide off the sorbent, wherein the sorbent comprises a hydroxamate resin. In one form, the target solution may comprise .sup.68Zn-enriched zinc nitrate. The method may further comprise the elution of the radionuclide off the sorbent using hydrochloric acid, wherein an amount of eluent of 5 milliliters or less can be used. This method may take 30 minutes or less.

(9) The method may further comprise adjusting pH of the solution including the radionuclide before passing the solution including the radionuclide through the column. In one version, these adjustments of the pH may comprise a dilution of the solution with water. The volume of water for dilution may range from 10 to 50 milliliters. In another version, the adjusting of the pH may comprise an addition of an organic or inorganic base to the solution. In this other version, the base may form a water soluble product with .sup.68Ga and .sup.68Zn. In one form of this other version, the base is sodium bicarbonate. The pH of the solution including the radionuclide before passing the solution including the radionuclide through the column may be between 5 and 7, preferably in a range of 5.5 to 6.5.

(10) In this third embodiment, at least one of the steps of the method may be completed by an automated process using a remotely controlled radiochemistry module for processing in a hot cell as depicted in FIG. 1. The yield of the radionuclide from the solution including the radionuclide may be greater than 80% by radioactivity, or greater than 85% by radioactivity, or greater than 90% by radioactivity, or greater than 95% by radioactivity. In another form, the hydroxamate resin may comprise hydroxamate groups bonded to a backbone comprising a material selected from the group consisting of silica, polymer coated silica, polyacrylate, and polystyrene. In one non-limiting form, the hydroxamate resin comprises hydroxamate groups bonded to a backbone comprising an acrylic acid/acrylamide coated silica having a diol bonded phase. The hydroxamate resin may have a particle size in a range of 10 to 100 microns, or in a range of 20 to 70 microns, or in a range of 30 to 60 microns. In one non-limiting form, the hydroxamate resin has a particle size in a range of 37 to 55 microns.

EXAMPLES

(11) The following Examples are provided in order to demonstrate and further illustrate certain embodiments and aspects of the present invention and are not to be construed as limiting the scope of the invention.

Example 1

Introduction to Example 1

(12) Hydroxamate mediated separation of Ga-68 from Zn-68 reduces processing time and provides a smaller volume of final eluent. Without limiting the present disclosure to a particular theory, it is contemplated that because Ga.sup.3+ forms a hard Lewis acid in solution that it should form stable complexes with hard Lewis base groups, e.g., N, O groups of hydroxamate. In contrast, zinc forms a borderline Lewis acid, which has less of a chemical affinity for the hydroxamate resin. Efficient trapping on a small volume of hydroxamate resin should also facilitate the reduction of final elution volumes to provide more concentrated solutions of Ga-68 for radiolabeling. Experiments were performed according to the following procedure.

Materials and Methods

Chemicals

(13) Zn-68 (99.23%) enriched metal was purchased from Cambridge Isotopes Laboratory (Tewksbury, Mass.). Hydrochloric acid (34-37% as HCl) and nitric acid (67-70% as HNO.sub.3) both trace metals basis were purchased from Fisher Scientific (Suwanee, Ga.). AG-50W-X8 (polystyrene-divinylbenzene sulfonic acid resin, 200-400 mesh, hydrogen form) resin was purchased from Bio-Rad (Hercules, Calif.). Accell Plus CM (300 Å, WAT 010740) cation exchange resin (acrylic acid/acrylamide coated silica having a diol bonded phase—particle size: 37-55 μm—pore size: 300 angstroms) was purchased from Waters Inc. (Milford, Mass.). The activity readings were measured using a CRC dose calibrator (#416 setting, CRC-55tPET, Capintec, Ramsey, N.J.).

Synthesis of Hydroxamate Resin

(14) Synthesis of hydroxamate resin was performed using a method developed by Pandey et al. [see Ref. 17 which is hereby incorporated by reference in the present disclosure]. Briefly, the hydroxamate resin was synthesized by stirring Accell Plus CM resin (2.00 g), methyl chloroformate (2.0 mL, 25.8 mmol) and triethylamine (2.0 mL, 14.3 mmol) in anhydrous dichloromethane (30 mL) at 0° C. for 30 minutes and then at room temperature for additional 90 minutes. The temperature of the mixture was further lowered to 0° C. before addition of hydroxylamine hydrochloride (0.6 g, 8.63 mmol) and triethylamine (2.0 mL, 14.3 mmol). The resultant mixture was stirred at room temperature for an additional 15 hours. The solvent was removed under vacuum, and cold water was poured with constant stirring into the flask containing the functionalized resin. The resin was filtered, washed extensively with water, and dried under vacuum.

(15) Hydroxamate resin can also be prepared on various types of backbone polymers/resins including but not limited to polystyrene, silica, polyacrylate, polymer coated with silica or any other organic/inorganic backbone materials. Furthermore, the high degree of hydroxamate functionalization on any back bone polymer with different mesh sizes (bead size) enhances the separation of Ga-68/67 from Zn-68.

Results and Discussion

Isolation of .SUP.68.Ga

(16) A solution including .sup.68Ga was produced in a solution target via 30 minute proton irradiation (current=20 μA) of a solution of 1.7 M .sup.68Zn-zinc nitrate (99.23% isotopic enrichment) in 0.2 N nitric acid using a method developed by Pandey et al. [see Ref. 16 which is hereby incorporated by reference in the present disclosure]. A column loaded with 100 mg of the hydroxamate resin as synthesized above was pre-washed with 1 mL of acetonitrile and 10 mL of water. After irradiation, the contents of the cyclotron target was delivered to a collection vial pre-loaded with 25 mL of 20 mM NaHCO.sub.3. The pH of the resultant solution (after addition of acidic target solution) was found to be in the range 5.5-6.5 for effective trapping of .sup.68Ga on the hydroxamate resin. The neutralized target solution was passed through the hydroxamate resin to trap .sup.68Ga, while allowing .sup.68Zn and shorter lived isotopes .sup.13N, .sup.11C to pass through. Further rinsing of the parent .sup.68Zn from the column was performed using 50 mL of water (pH 5.5). All .sup.68Zn containing fractions were collected in a recovery vial for recycling of the parent .sup.68Zn isotope. Finally, .sup.68Ga was eluted from the hydroxamate resin with 2 mL 2 M hydrochloric acid and collected in a product vial for subsequent labeling.

(17) This process was automated using a remotely controlled radiochemistry module for processing in a hot cell as depicted in FIG. 1. A programmable microprocessor-based controller was in electrical communication with valves V of the system 100 of FIG. 1 to open and close the valves when necessary to transfer fluids in the fluid lines L of FIG. 1. Suitable timing of valve opening and closing was programmed in the controller. The processing was achieved in approximately 20 minutes with greater than 80% yield, decay corrected to start of processing.

(18) Using the radiochemistry module as depicted in FIG. 1 with the hydroxamate resin as synthesized above, processing times of 20-25 minutes can provide a trapping efficiency of 70-90%, an elution efficiency of 95-98%, and an overall efficiency of 70-90%.

(19) An analysis of metal impurities in the .sup.68Ga product was as follows: Ga: 0.3±0.1 μg, Cu: 10.2±7.3 μg, Zn: 33.3±21 μg, and Fe: 31.9±26.2 μg for an ICP-MS analysis of ten different batches.

Recycling of .SUP.68.Zn

(20) Economical production of .sup.68Ga from a cyclotron requires efficient recycling of the parent isotope .sup.68Zn. A method of recycling of .sup.68Zn was also developed. The pH of the recovered .sup.68Zn solution (above) was adjusted to pH=5.0 by addition of nitric acid. The resultant .sup.68Zn solution was passed through a column containing 1.5 grams of cation exchange resin (Bio-Rad AG-50W-X8, 200-400 mesh, hydrogen form). Prior to use, the cation exchange resin was washed with 60 mL of water followed by 20 mL of air. .sup.68Zn was trapped on the cation exchange resin. The resin was washed with an additional 10-15 mL of water (pH 5.0-5.5) with minimal loss of .sup.68Zn. Finally, .sup.68Zn was eluted from the resin with 15 mL of 8 M HNO.sub.3. The recovered .sup.68Zn nitrate solution was dried under vacuum for subsequent use to produce .sup.68Ga. .sup.68Zn recovery was found to exceed 98%. ICP-MS analysis of the recovered .sup.68Zn showed presence of insignificant quantities of metal ion impurities, such as sodium.

(21) Thus, an improved method of Ga-68 purification and .sup.68Zn recovery have been achieved. The developed method further simplifies a solution target approach of .sup.68Ga production.

Example 2

(22) Hydroxamate mediated separation of .sup.68Ga from .sup.68Zn is facilitated by a pH adjustment of the target solution. As will be detailed below, the separation of .sup.68Ga from .sup.68Zn has been accomplished in two different ways.

Non-Base Mediated pH Adjustment

(23) First, a non-base mediated pH adjustment was performed through dilution of post-irradiated .sup.68Ga target solution with water. Various quantities of water were used to achieve different pH values before trapping .sup.68Ga on hydroxamate resin. The amount of water used to adjust pH increases with increasing strength of the nitric acid and/or molarity of the .sup.68Zn solutions used in target irradiation. Results are shown below in Table 1.

(24) TABLE-US-00001 TABLE 1 Summary of the Non-Base Mediated Purification of Ga-68 from the Zn-68 Run # 1 2 3 4 5 Solution 0.5M salt in 0.8N HNO.sub.3 composition Irradiation 45 μA, 30 min 45 μA, 60 min condition Hydroxamate 700 mg 700 mg 250 mg 250 mg 750 mg (mg) (modified) Amount of 15.0 mL water used (mL) Turbidity/ No No No No No precipitate % of activity  9.5% 18.9% 14.2%  9.6% 23.1% as Product % of activity 88.5% 76.9% 84.3% 88.3% 63.4% in Zn-68 recovery vial % of activity  2.0%  4.1%  1.3%  2.1% 13.5% retained on hydroxamate

Base Mediated pH Adjustment

(25) Various organic and inorganic bases were employed to achieve a desired pH of the target solution before trapping .sup.68Ga on hydroxamate resin. Herein, we demonstrated the use of sodium bicarbonate to achieve the desired pH. The amount of base (bicarbonate or appropriate organic/inorganic base) used to adjust pH is dependent upon the strength of the nitric acid and molarity of the .sup.68Zn solutions used in target irradiation. Higher concentrations of nitric acid and .sup.68Zn nitrate salt required higher strength of base solution to adjust the pH to the desired level (pH between 5.5 and 6.5). The selection of base also depends upon the solubility of the resultant species formed after neutralization. If the resultant species formed are insoluble in aqueous solution, then they cannot be used for automated separation of .sup.68Ga from parent .sup.68Zn. For example, if the acidic post-irradiation target solution is neutralized with sodium hydroxide, then the resultant species formed will be zinc hydroxide and gallium hydroxide. The hydroxides of Ga and Zn are poorly soluble in water and therefore, would not be appropriate. Similar rationale can be applied to other organic/inorganic bases before their use in this hydroxamate based method of separation of .sup.68Ga from .sup.68Zn. Sodium bicarbonate was chosen because it yields sodium nitrate, carbonic acid and zinc bicarbonate after neutralization and allows .sup.68Zn nitrate to be obtained effectively during the recycling process. Results are shown below in Table 2.

(26) TABLE-US-00002 TABLE 2 Summary of the Base Mediated Purification of Ga-68 from the Zn-68 Run # 1 2 3 4 5 6 7 8 9 Solution 0.5M salt in 1.0M salt in 0.8N HNO.sub.3 1.0M salt 1.0M salt in 1.5N HNO.sub.3 composition 0.8N HNO.sub.3 in 1.25N HNO3 Irradiation 30 μA, 40 μA 20 μA, 30 μA, 40 μA, 30 μA, 40 μA 30 μA, 60 min condition 60 min 60 min 60 min 60 min 60 min 60 min 60 min Hydroxamate 100 mg (mg) (modified) pH (after 6.0 5.86 5.96 6 5.9 5.92 5.96 5.94 5.95 neutralization) O•13N NaHCO.sub.3 14.3 12.9 21.0 25.4 25.4 (mL) Turbidity/ No No No No No No No no no precipitate % of activity as 69.34 68.53 82.49 86.10 71.26 89.80 73.94 76.18 80.49 Product % of activity in 28.50 29.21 13.65 10.07 27.26 7.83 19.82 21.88 5.06 Zn-68 recovery vial % of activity 2.16 2.26 3.86 3.83 1.48 2.37 6.25 1.94 14.44 retained on hydroxamate Note: 1. Activity lost in the lines and collection flask have not been included in the calculation. 2. These runs are processed after 2.5 to 3 hours post irradiation.

Recycling of .SUP.68.Zn

(27) Recycling of recovered .sup.68Zn(NO.sub.3).sub.2 was performed on a cation exchange column using 1.5-1.6 grams of AG 50W-X8 resin. Prior to the recycling of .sup.68Zn, an AG 50W-X8 resin column was washed with 60 mL of deionized water dropwise followed by 20 mL of air. Before passing the recovery solution through the column, the pH of the recycling solution was adjusted to ≤5 using dilute nitric acid, if needed. After passing the recovery solution through the column, 20 mL of air was also pushed through. The column was washed with 10 mL of deionized water, followed by 20 mL of air. .sup.68Zn was eluted with 15 mL of 8N HNO.sub.3 into a fresh vial, and followed by 20 mL of air. The obtained .sup.68Zn nitrate solution was concentrated on a rotary evaporator. The column was regenerated by passing an additional 2 mL of concentrated HNO.sub.3 (15.9 N). To reuse this column, a step of activation with 60 mL of deionized water and a step of 20 mL of air were performed. Results are shown below in Tables 3-4.

(28) TABLE-US-00003 TABLE 3 % of Zn-68 nitrate recovered in comparison with known starting mass of zinc nitrate (Batch-1) Mass of Zinc Mass Found Nitrate After Recycling Molarity of Hexahydrate Concentration process Solution (M) Used (g) (g) Efficiency 1 0.5 0.330 0.293 2 0.5 0.330 0.354 3 0.5 0.330 0.403 4 1 0.660 0.571 5 1 0.660 0.531 Total 2.310 2.152 93.2%

(29) TABLE-US-00004 TABLE 4 % of Zn-68 nitrate recovered in comparison with known starting mass of zinc nitrate (Batch-2). Mass of Zinc Mass Found Nitrate After Recycling Molarity of Hexahydrate Concentration process Solution (M) Used (g) (g) Efficiency 1 1 0.660 0.629 2 1 0.660 0.737 3 1 0.660 0.470 4 1 0.660 0.590 Total 2.640 2.426 91.9%

REFERENCES

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(31) The citation of any document or reference is not to be construed as an admission that it is prior art with respect to the present invention.

(32) Thus, the present invention provides improved methods and systems for rapid isolation of cyclotron produced radionuclides, such as .sup.68Ga. The methods of processing .sup.68Ga and recycling of .sup.68Zn offer an economical alternative to .sup.68Ge/.sup.68Ga generators.

(33) Although the invention has been described with reference to certain embodiments, one skilled in the art will appreciate that the present invention can be practiced by other than the described embodiments, which have been presented for purposes of illustration and not of limitation. Therefore, the scope of the appended claims should not be limited to the description of the embodiments contained herein.