Astatine purification method

Abstract

This provides a rapid and more effective method for recovering At. [Solution] A method for isolating astatine, comprising the steps of (a) contacting a composition containing astatine and bismuth with nitric acid to form a first solution containing astatine, bismuth, and nitric acid; (b) contacting a resin with the first solution to separate the astatine from the first solution and distribute it to the resin; and (c) eluting the astatine from the resin. The composition containing astatine may have the formula AtO+X- (where X- is a counterion).

Description

[Technical Field]

[0001] This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application 63 / 003,335, filed on April 1, 2020, the contents of which are incorporated herein by reference.

[0002] This invention was implemented with government support under the DOE-Office of Science DE-SC0020958. The government has certain rights to this invention. [Background technology]

[0003] Targeted alpha-emitting radiotherapy (TAT) is a treatment for metastatic castration-resistant prostate cancer. 223 Following the success of Xofigo®, based on RaCl2, significant interest has been gained. The promising performance of Xofigo® indicates a need to expand the catalog of usable alpha-emitting radionuclides. One such isotope that has attracted much attention is 211 It is At, and with a moderately short half-life of 7.2 hours and quantitative alpha emission from a simple decay scheme, it has decay characteristics well suited to clinical settings. There are only about 30 cyclotrons in the world capable of producing usable amounts, seven of which are in the United States, and one of them is currently a supplier to the US Department of Energy's Isotope Program, 211 At suppliers remain limited. Collisions between natural Bi targets and alpha particles in the energy range of 28.5–31 MeV are 209 Bi(α,2n) 211 Through the At nuclear reaction, the usable amount 211 It is adopted as a criterion for generating At. Despite its low availability, 211 At is being used in numerous clinical trials investigating the treatment of malignant brain tumors and ovarian cancer, as well as in current research to treat advanced hematopoietic malignancies.

[0004] Furthermore, generally, the chemistry of At is one of the few relatively unexplored areas in the periodic table. This may be due to the fact that, since astatine has no stable isotopes, the terrestrial abundance of At is estimated to be only 0.07 g, the lowest among all naturally occurring elements. The longest half-life is only about 8.1 hours for 210 At, and 211 exists slightly longer than At. Astatine is the fifth member of the halogen group and the heaviest confirmed member among the metalloids, enabling a rich and diverse chemistry. As examples, various oxidation states of At - At, 0 At, + At, 3+ At, 5+ At and 7+ At have been observed, but a detailed description of their chemistry and chemical species is hampered by the barrier around limited supply. The electronic structure is complicated by the relativistic effects of this relatively heavy (atomic radius ~0.45 Å) element (Z = 85), which undergoes significant spin-orbit interactions, posing problems for the prediction of its chemical dynamics based on computer models that ignore spin-orbit interactions. On the contrary, including spin-orbit interactions requires much more computer resources and special treatment of the models to ensure the accuracy of the prediction. Many properties and complexes of At are affected by including spin-orbit interactions in such predictions, including polarizability, electronegativity, shifts in vibrational frequencies, and changes in dipole moments.

[0005] Motivated by exploring the uncharted areas of the periodic table, the use of radiopharmaceuticals, or understanding At itself, rapid and efficient separation and purification for the isolation and recovery of this interesting element are very important. Historically, two methods, dry distillation and wet chemical treatment, have been used to recover 211 At from Bi targets. The latter has been shown to produce a more reproducible 211 yield of At. In analytical-scale separations, macro amounts of Bi (1 - 10 g), which occupy most of the matrix, are recovered and purified 211For At amounts on the order of 1-10 ng, solvent extraction is not a useful and efficient means of separation because it limits the separation step to one per contact and requires advanced equipment to operate in continuous flow mode. Chromatography, on the other hand, can provide numerous steps on a single column and is inherently operated in continuous flow mode.

[0006] Woen et al. (Inorg. Chem. 59 (2020) 6137-6146) and Li et al. (Sci. Rep. 9 (2019) 16960) both achieved yields of 68% using pre-filtration resin and 95% using tellurium metal powder. 211 At collide 209 We recently demonstrated an efficient chromatography system for recovering Bi targets. US 2018 / 0308599 also used chromatography. 211 Methods for isolating At are described. However, these methods require a system for converting the nitrate to a chloride medium and involve slow, time-consuming steps, either by evaporation to dryness to remove the nitrate or by chemical decomposition of the nitrate with ammonium chloride hydroxide. Therefore, a rapid and more efficient method for recovering At is urgently needed. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] US 2018 / 0308599 [Non-patent literature]

[0008] [Non-Patent Document 1] Inorg. Chem. 59 (2020) 6137-6146 [Non-Patent Document 2] Sci. Rep. 9 (2019) 16960 [Overview of the Initiative] [Means for solving the problem]

[0009] One aspect of the present invention is, (a) A step of contacting a composition containing astatine and bismuth with nitric acid to form a first solution containing astatine, bismuth and nitric acid. (b) A step of contacting the resin with the first solution to separate astatine from the first solution and to distribute it into the resin, (c) A method comprising the step of eluting astatine from the resin.

[0010] In another aspect, composition, AtO + X ‐ (X ‐ It includes (which is the counterion).

[0011] Further embodiments, features, and advantages of the present invention will become apparent through the following detailed description and implementation of the invention. Methods and compounds of the present invention may be described as embodiments of any of the following enumerated sections. Any embodiment described herein may be used in conjunction with other embodiments described herein, to the extent that the embodiments are not inconsistent with each other.

[0012] 1. (a) A step of contacting a composition containing astatine and bismuth with nitric acid to form a first solution containing astatine, bismuth and nitric acid. (b) A step of contacting the resin with the first solution to separate astatine from the first solution and to distribute it into the resin, (c) A method comprising the step of eluting astatine from the resin.

[0013] 2. The method according to item 1, wherein the resin is impregnated with a solvent.

[0014] 3. The method according to item 1 or 2, wherein the solvent includes an organic solvent.

[0015] 4. The method according to any one of items 1 to 3, wherein the organic solvent is polar.

[0016] 5. The organic solvent is optionally substituted with C1-C 18 The method according to any one of claims 1 to 4, comprising an alkyl group.

[0017] 6. The method according to any one of items 1 to 5, wherein the organic solvent contains a carbonyl.

[0018] 7. The method according to any one of claims 1 to 6, wherein the organic solvent comprises an aldehyde, ketone, ester, amide, carbonate, carboxylate, or carbamate.

[0019] 8. The method according to any one of claims 1 to 7, wherein the organic solvent is of the formula C1-C6 alkyl-C(O)-C1-C6 alkyl, and each hydrogen atom of the C1-C6 alkyl is optionally substituted.

[0020] 9. The method according to any one of items 1 to 8, wherein the organic solvent is octanone.

[0021] 10. The method according to any one of items 1 to 9, wherein the organic solvent is 3-octanone.

[0022] 11. The organic solvent is C1~C 18 The method described in any one of items 1 to 5, which is an alkanol.

[0023] 12. The method according to any one of claims 1 to 11, wherein the astatine has a D-value partition coefficient of at least 20 in the organic solvent.

[0024] 13. The method according to any one of claims 1 to 12, wherein the astatine has a D-value partition coefficient of at least 40 in the organic solvent.

[0025] 14. The method according to any one of claims 1 to 13, wherein the astatine has a D-value partition coefficient of at least 60 in the organic solvent.

[0026] 15. The method according to any one of claims 1 to 14, wherein the astatine has a D-value partition coefficient of at least 80 in the organic solvent.

[0027] 16. The method according to any one of items 1 to 15, wherein the resin is an inert resin.

[0028] 17. The method according to any one of claims 1 to 16, wherein the resin is a polymer resin, a zeolite, a molecular sieve, or a porous glass bead.

[0029] 18. The method according to any one of claims 1 to 17, wherein the resin comprises a styrene-divinylbenzene copolymer.

[0030] 19. The method according to item 18, wherein the benzene does not contain a functional group.

[0031] 20. The astatine mentioned above, 211 The method described in any one of items 1 to 19, wherein At.

[0032] 21. The astatine mentioned above, 209 The method described in any one of items 1 to 20, wherein At.

[0033] 22. The method according to any one of claims 1 to 21, wherein the bismuth is not distributed into the resin.

[0034] 23. The method according to any one of claims 1 to 22, wherein the nitric acid in the first solution is at a concentration of about 1 M to about 10 M.

[0035] 24. The method according to any one of claims 1 to 23, wherein the nitric acid in the first solution is concentrated at a concentration of about 1 M to about 8 M.

[0036] 25. The method according to any one of claims 1 to 24, wherein the nitric acid in the first solution is concentrated at a concentration of about 2 M to about 8 M.

[0037] 26. The method according to any one of claims 1 to 25, further comprising the step of washing the resin after step (b).

[0038] 27. The method according to items 1 to 26, wherein the cleaning step is carried out by passing an aqueous solution through the resin.

[0039] 28. The method according to item 27, wherein the aqueous solution contains an acid.

[0040] 29. The method according to item 28, wherein the acid is nitric acid, hydrobromic acid, hydrochloric acid, sulfuric acid, or perchloric acid.

[0041] 30. The method according to item 28 or 29, wherein the concentration of the acid is about 1 M to about 10 M.

[0042] 31. The method according to any one of claims 1 to 30, for recovering 85% or more of astatine from a mixture.

[0043] 32. The method according to any one of items 1 to 31, for recovering 90% or more of astatine from the mixture.

[0044] 33. The method according to any one of items 1 to 32, for recovering 95% or more of astatine from a mixture.

[0045] 34. The method according to any one of claims 1 to 33, wherein the astatine has a purity of 90% or more after step (c).

[0046] 35. The method according to any one of claims 1 to 34, wherein the astatine has a purity of 95% or more after step (c).

[0047] 36. The method according to any one of claims 1 to 35, wherein the astatine has a purity of 99% or more after step (c).

[0048] 37. The method according to any one of claims 1 to 36, wherein the elution step is carried out by contacting the resin with a second organic solvent.

[0049] 38. The second organic solvent is acetone or C1-C 18 The method described in item 37, including alkanols.

[0050] 39. The method according to item 38, wherein the second organic solvent comprises ethanol.

[0051] 40. The method according to claims 37-39, wherein the second organic solvent can be miscible in the first organic solvent.

[0052] 41. The method according to any one of items 1 to 40, wherein steps (a), (b), and (c) are carried out in less than approximately one hour.

[0053] 42. The method according to any one of items 1 to 41, wherein steps (a), (b), and (c) are carried out in less than approximately 30 minutes.

[0054] 43. The method according to any one of items 1 to 42, wherein steps (a), (b), and (c) are performed in less than approximately 15 minutes.

[0055] 44. The method according to any one of items 1 to 43, wherein steps (a), (b), and (c) are performed in less than approximately 10 minutes.

[0056] 45. The method according to any one of claims 1 to 44, wherein steps (a), (b), and (c) are carried out in less than 20% of the half-life of astatine.

[0057] 46. ​​The method according to any one of claims 1 to 45, wherein steps (a), (b), and (c) are carried out in less than approximately 15% of the half-life of astatine.

[0058] 47. The method according to any one of claims 1 to 46, wherein steps (a), (b), and (c) are carried out in less than 10% of the half-life of the astatine.

[0059] 48. The method according to any one of claims 1 to 47, wherein steps (a), (b), and (c) are carried out at less than approximately 5% of the half-life of astatine.

[0060] 49. The method according to any one of claims 1 to 48, comprising the step of preparing the resin prior to step (b).

[0061] 50. The method according to claim 49, wherein the step of preparing the resin includes a step of contacting the resin with an organic solvent.

[0062] 51. The method according to any one of claims 1 to 50, further comprising the step of labeling the therapeutic agent with the eluted astatine.

[0063] 52. AtO + X ‐ (X ‐ A composition containing (where is a counterion).

[0064] 53.X ‐ The composition according to item 52, wherein the composition is a nitrate, halide, or perchlorate.

[0065] 54.X ‐ However, the composition described in item 53 is a nitrate.

[0066] 55.X ‐ However, the composition is perchlorate, as described in item 53.

[0067] 56.X ‐ However, the composition described in item 53 is a halide.

[0068] 57. The composition according to item 56, wherein the halide is a chloride.

[0069] 58. A composition according to any one of claims 52 to 57, which is compounded with an organic solvent.

[0070] 59. The organic solvent is optionally substituted with C1-C 18 The composition according to item 58, comprising an alkyl group.

[0071] 60. The composition according to item 58, wherein the organic solvent comprises a carbonyl.

[0072] 61. The composition according to item 58, wherein the organic solvent comprises an aldehyde, ketone, ester, amide, carbonate, carboxylate, or carbamate.

[0073] 62. The composition according to item 58, wherein the organic solvent is of the formula C1-C6 alkyl-C(O)-C1-C6 alkyl, and each hydrogen atom of the C1-C6 alkyl is optionally substituted.

[0074] 63. The composition according to item 58, wherein the organic solvent is octanone.

[0075] 64. The composition according to item 58, wherein the organic solvent is 3-octanone.

[0076] 65. The astatine mentioned above, 211 A composition according to any one of claims 52 to 64, wherein At.

[0077] 66. The astatine mentioned above, 209 A composition according to any one of claims 52 to 64, wherein At.

[0078] 67. A composition according to any one of items 52 to 66, manufactured by the method described in any one of items 1 to 51.

[0079] 68. A composition comprising astatine, prepared by any one of the methods described in Sections 1 to 51.

[0080] 69. A method comprising the steps described in any one of paragraphs 1 to 51.

[0081] 70. A method that essentially consists of the processes described in any one of paragraphs 1 through 51.

[0082] Further features of the present invention will become apparent to those skilled in the art by examining exemplary embodiments that illustrate the best mode of carrying out the present invention as currently recognized. [Brief explanation of the drawing]

[0083] [Figure 1] Figure 1 shows the D values ​​for extraction of 211At into various organic solvents as a function of the initial aqueous HNO3 concentration. The solid line is for visual aids. Note that the D value for Bi is 0.05 or less in all cases. [Figure 2] Figure 2 shows the TGA curves for Amberchrom® CG300M resin before impregnation (blue) and impregnated with 1-octanol and 3-octanone. [Figure 3] Figure 3 shows the amount of 3-octane impregnated (■) and the percentage of total impregnation (◆) in the fractions recovered from 3-octanone-impregnated Amberchrom® CG300M resin beds (0.5 mL BV, 7 mm ID × 13 mm height), calculated from TOC analysis. The arrows indicate the axes corresponding to each dataset. [Figure 4] Figure 4 shows the chromatogram of a 0.5 mL aliquot of 2 M HNO3 containing 20 μL of Run 1 spike (approximately 13 μCi211 At) dissolved in a collision target solution on a 1-octanol-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: Data were attenuated to account for differences in half-lives, and Bi was determined by ICP-MS. [Figure 5] Figure 5 shows the chromatogram of a 0.5 mL aliquot of 2 M HNO3 containing 20 μL of Run 1 spike (approximately 13 μCi211 At) dissolved in a collision target solution on a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: Data were attenuated to account for differences in half-lives, and Bi was determined by ICP-MS. [Figure 6]Figure 6 shows the chromatogram of a 0.5 mL aliquot of 6 M HNO3 containing 20 μL of Run 1 spike (approximately 13 μCi211 At) dissolved in a collision target solution on a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: Data were attenuated to account for differences in half-lives, and Bi was determined by ICP-MS. [Figure 7] Figure 7 shows the chromatogram of a 1.5 mL aliquot of 2 M HNO3 containing a collision target and 399 μL of Run 2 spikes (~1.0 mCi 211 At) dissolved with 42 μL of 207Bi spikes (approximately 10 nCi) on a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: The dead volume was assumed to be half of the BV, but this appears to have been an overestimation as small amounts of 207Bi and 66 / 67Ga were observed in the fractionation. The data was corrected for decay to explain the difference in half-lives. [Figure 8] Figure 8 shows the chromatogram of a 1.4 mL aliquot of 4 M HNO3 containing 399 μL of Run 2 spikes (~1.0 mCi 211 At) dissolved in a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height) containing a collision target and 42 μL of 207Bi spike (approx. 10 nCi). Note: The dead volume was assumed to be half of the BV, but this appears to have been an overestimation as small amounts of 207Bi and 66 / 67Ga were observed in the fractionation. The data was corrected for decay to explain the difference in half-lives. [Figure 9]Figure 9 shows the chromatogram of a 1.3 mL aliquot of 5.7 M HNO3 containing 399 μL of Run 2 spikes (~1.0 mCi 211 At) dissolved in a collision target solution and 42 μL of 207Bi spikes (approximately 10 nCi) on a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: The dead volume was assumed to be half of the BV, but this appears to have been an overestimation as small amounts of 207Bi and 66 / 67Ga were observed in the fractionation. The data was corrected for decay to explain the difference in half-lives. [Figure 10] Figure 10 shows the chromatogram of a 5 mL aliquot of Run 1, prepared by dissolving a collision target solution (approximately 6 M HNO3, 4.1 mCi211 At) in a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: Data were attenuated to account for differences in half-lives, and Bi was determined by ICP-MS. [Figure 11] Figure 11 shows the chromatogram of a 4 mL aliquot of 5.9 M HNO3 containing 3.76 mL of Run 2 spikes (approximately 9.8 mCi 211 At) dissolved in a collision target solution and 240 μL of 207Bi spikes (~57.6 nCi) on a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). Note: The dead volume was assumed to be half of the BV, but this appears to have been an overestimation as small amounts of 207Bi and 66 / 67Ga were observed in the fractionation. The data was corrected for decay to explain the difference in half-lives. [Modes for carrying out the invention]

[0084] Astatine (At) may be useful as a radiolabel for therapeutic purposes. However, natural abundance of At is low. At can be produced by impacting a bismuth (Bi) metal target with alpha particles. The produced At must then be isolated from unreacted Bi. This specification describes a method for isolating At from a composition, such as a composition formed from the impacted Bi, using chromatography. In exemplary embodiments, the method described herein involves dissolving the At-containing composition and then isolating At from the dissolved mixture. The method described may be carried out without the need to change the medium or solution used to initially dissolve the At / Bi composition.

[0085] In this specification, At refers to 209 At or 211 It may be At and its cation species. For example, At as described in the methods herein is the cation species AtO + It may be written as At, but it will be written as At. For example, the method may include manufacturing At. At is 209 When Bi metal is hit by alpha particles, 209 Bi(α,2n) 211 It may be produced by a nuclear reaction of At. The resulting collision target may contain a mixture of At, unreacted Bi, and by-products.

[0086] In some embodiments, At is isolated from a composition containing Bi and At. Exemplarily, the composition is brought into contact with a solution, such as an aqueous solution. In exemplary embodiments, the aqueous solution contains an acid, such as an organic or inorganic acid. The inorganic acid may be nitric acid. The solution dissolves or substantially dissolves the composition to form a solution containing At and Bi. In some embodiments, the solution contains At, Bi, and an acid. In some embodiments, the solution contains At, Bi, and nitric acid.

[0087] In some embodiments, the solution has a specific concentration of acid or is prepared to have a specific concentration of acid before a subsequent step. Exemplarily, the acid may be useful when dissolving the composition. For example, the presence of nitric acid may be useful when dissolving a collision Bi target.

[0088] Exemplary, the acid concentration may be about 1 M to about 10 M, about 1 M to about 8 M, about 2 M to about 8 M, or about 3 M to about 7 M. The acid concentration may be about 1 M, about 2 M, about 3 M, about 4 M, about 5 M, about 6 M, about 7 M, about 8 M, about 9 M, or about 10 M. The acid concentration may be adjusted according to the partition coefficient in the solvent used in subsequent steps. The ranges described herein are equally applicable when the acid is an organic acid or an inorganic acid such as nitric acid.

[0089] In some embodiments, At is isolated using chromatography. In exemplary embodiments, chromatography is carried out by using a resin. The resin may be in the form of a resin bed. The resin bed may be in a column. Alternatively, the resin may be used in a bulk process. Exemplary resins include polymer resins and glass resins. In some embodiments, the resin includes zeolites, molecular sieves, polymer resins, or glass resins. In some embodiments, the resin is porous. In some embodiments, the porous resin is a polyacrylate resin or porous glass beads. The resin may be inert. In some embodiments, the resin includes a styrene-divinylbenzene copolymer. In some embodiments, the benzene in the copolymer does not contain functional groups.

[0090] In some embodiments, the method includes a step of preparing the resin. This step may occur before contacting the resin with a solution containing At. In exemplary embodiments, the resin may be contacted with a solvent such as an organic solvent. Exemplarily, the step of preparing the resin involves recovering the resin impregnated with the solvent such as an organic solvent. In some embodiments, the organic solvent is polar. In some embodiments, the organic solvent is C1-C 18Each hydrogen atom of the alkyl group is optionally substituted by a functional group, or optionally substituted C1-C 18 Contains alkyl. C1~C 18 Optional substituents on alkyl groups are known in the art and include halogens, hydroxyls, amines, thiols, oxos, ketones, carboxylates, aldehydes, amides, carbonates, carbamates, and combinations thereof. In some embodiments, the organic solvent includes aldehydes, ketones, esters, amides, carbonates, carboxylates, or carbamates. In some embodiments, the organic solvent includes C1-C12 18 , C1~C 12 or contains C1-C6 alkyl. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)-C1-C6 alkyl. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)-C1-C6 alkyl, where each hydrogen atom of the C1-C6 alkyl is optionally substituted. In some embodiments, the organic solvent is octanone. In some embodiments, the organic solvent is 3-octanone. In some embodiments, the organic solvent is C1-C 18 It is an alkanol. Exemplarily, the organic solvent may include a mixture of the organic solvents described herein.

[0091] The term "alkyl" refers to a monovalent hydrocarbon group that is either straight-chain or branched-chain. In some embodiments, the number of atoms in "alkyl" is C1-C1. 18 Alkyl, C1-C 12It may be beneficial to limit the alkyl group to a specific range of atoms, such as alkyl or C1-C6 alkyl groups. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, and isohexyl, and any group that can be considered equivalent to any one of the above examples in light of the usual art and the teachings provided herein. Alkyl groups may be unsubstituted or substituted as described herein. Alkyl groups may be substituted with substituents in any of the various embodiments, including one or more substituents, as described herein. The term “alk” may form a prefix with the rest, which are functional groups. For example, “alkanol” is an alkyl group substituted with an alcohol.

[0092] The term "substituted" means that a particular group or part has one or more substituents. The term "unsubstituted" means that a particular group has no substituents. When the term "substituted" is used to describe a structural system, substitution means that it occurs at any valence position allowed in the system. In some embodiments, "substituted" means that a particular group or part has one, two, or three substituents. For example, two hydrogen atoms on the carbon of an alkyl group may be substituted by an oxo (=O) group to form a carbonyl (C=O). In other embodiments, "substituted" means that a particular group or part has one or two substituents. In other embodiments, "substituted" means that a particular group or part has one substituent.

[0093] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0094] In some embodiments, the solvent of the impregnated resin is a solvent that provides a D-value partition coefficient of At of at least 10 to an aqueous solution, such as an aqueous solution containing nitric acid. In exemplary embodiments, At has a D-value partition coefficient of at least about 20, at least about 40, at least about 60, or at least about 80 in an organic solvent. Exemplarily, the partition coefficient may be measured to an aqueous solution containing an acid such as nitric acid. In some embodiments, At has a partition coefficient of at least about 20 or at least about 40 between octanone and an aqueous solution containing about 2 to 6 M nitric acid.

[0095] In some embodiments, the At composition is supported on the resin in a volume of solution relative to the volume of the resin bed. In some embodiments, the solution containing At is supported on the resin bed in a ratio of floor volumes up to about 10, up to about 8, up to about 6, or up to about 4. The number of floor volumes used for supporting the At composition may be adjusted by means known in the art to maximize the amount of At distributed in the resin.

[0096] Exemplary, At may come into contact with the resin, and At may be distributed into the resin, forming a complex or otherwise forming a favorable interaction with the resin. Exemplary, even if Bi comes into contact with the resin, Bi will not be retained in or on the resin. Alternatively, Bi may form a weak interaction with the resin such that any bound or retained Bi is removed when the resin is washed. It should be understood that contact includes any form of chemical interaction, such as ionic or non-covalent interactions. Furthermore, it should be understood that distribution into the resin includes distribution into the internal space of the resin as well as contact with the surface of the resin, and the formation of a favorable interaction that retains At in the resin.

[0097] After contacting the resin with a solution containing a mixture containing At, the resin may be washed. The washing step may include washing the resin with an aqueous solvent. In some embodiments, the aqueous solvent contains an acid. In some embodiments, the aqueous washing solution contains an acid at a lower concentration than the acid used to dissolve the At / Bi composition. For example, if the acid concentration in the aqueous solution in which the At / Bi composition was dissolved is about 6 M, the acid concentration in the washing solution may be less than about 6 M, for example, about 2 M. In some embodiments, the acid concentration is less than about 10 M, less than about 8 M, less than about 6 M, or less than 4 M. In some embodiments, the acid concentration is up to about 8 M, up to about 6 M, or up to about 4 M. In exemplary embodiments, the acid used in the washing step is the same acid as the acid in the previous step, for example, nitric acid.

[0098] Alternatively, the acid may be any of the following: for example, the acid may be HClO4, HCl, HBr, or H2SO4. Exemplarily, a change in the acid used in the washing step may change the counterions of the isolated At recovered in the elution step.

[0099] In some embodiments, the resin cleaning process is measured as a ratio of floor volumes. For example, the resin may be cleaned with a solution having a volume of at least about 2, at least about 3, at least about 4, at least about 5, or at least about 6 floor volumes. In exemplary embodiments, the resin may be cleaned sequentially with an aqueous solution containing an acid and an aqueous solution without an acid. The cleaning process may be prepared by means known in the art and may include further or fewer cleaning steps with aqueous solutions.

[0100] The method includes a step of eluting At from the resin, exemplary, the elution step dissociates At from the resin so that At can be recovered. The elution step may be carried out by contacting the resin with an organic solvent. In some embodiments, the organic solvent is the same as the solvent in which the resin was impregnated. In some embodiments, the organic solvent in the elution step can be miscible with the solvent in which the resin was impregnated. In some embodiments, the organic solvent is C1-C18 Each hydrogen atom of the alkyl group is optionally substituted by a functional group, or optionally substituted C1-C 18 Contains alkyl. C1~C 18 The optional substituents are known in the art and include halogens, hydroxyls, amines, thiols, oxos, ketones, carboxylates, aldehydes, amides, carbonates, carbamates, and combinations thereof. In some embodiments, the organic solvent includes aldehydes, ketones, esters, amides, carbonates, carboxylates, or carbamates. In some embodiments, the organic solvent includes C1-C12 18 , C1~C 12 Or it contains C1-C6 alkyl groups. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)-C1-C6 alkyl. In some embodiments, the organic solvent is of the formula C1-C6 alkyl-C(O)-C1-C6 alkyl, where each hydrogen atom of the C1-C6 alkyl is optionally substituted. In some embodiments, the organic solvent is octanone. In some embodiments, the organic solvent is 3-octanone. In some embodiments, the organic solvent is C1-C 18 It is an alkanol. In some embodiments, the organic solvent includes ethanol.

[0101] Exemplary, the methods described herein recover at least about 80%, at least about 85%, at least about 90%, or at least about 95% of At from an At-containing composition. In some embodiments, the methods recover about 80% to about 99%, about 85% to about 99%, or about 90% to about 99% of At from an At-containing composition.

[0102] Exemplary examples, the eluted At has a higher purity of At than the composition containing At prior to the chromatography step. In some embodiments, the eluted At has a purity of at least about 90%, at least about 95%, or at least about 99%.

[0103] The methods described herein may be carried out in less than about 1 hour, less than about 30 minutes, less than about 15 minutes, or less than about 10 minutes. Exemplarily, the methods are carried out in a shorter time compared to comparative methods that require the steps of dissolving the At / Bi composition in a nitric acid solution, evaporating the nitric acid solution, and reconstituting the residue in hydrochloric acid before chromatography, or compared to comparative methods that require the decomposition of the t nitrate before chromatography. The methods described herein isolate At at a specific proportion of its half-life. In some embodiments, the methods are: 211 The procedure is performed when the half-life of At, such as At, is less than approximately 20%, less than approximately 15%, less than approximately 10%, or less than approximately 5%.

[0104] In some embodiments, the method may further include labeling the therapeutic agent with eluted At. This may be carried out directly in a column fraction of the eluted At, or it may include concentrating the At-containing fraction and dissolving or suspending the At in a solution used in the labeling step.

[0105] In another aspect, composition, X - AtO is the counterion. + X - Contains a salt. The counterion may be the conjugate base of the aqueous acid used in the method described herein, or the conjugate base of any preferred acid. In some embodiments, X - X is a nitrate, halide, or perchlorate. In some embodiments, X - is a nitrate. In some embodiments, X - is a halide. Preferred halides include fluorides, chlorides, or bromides. In some embodiments, X - This is a perchlorate. In some embodiments, AtO + At is, 211 At or 209 It is At. [Examples]

[0106] material Nitric acid (67-70% Aristar® Plus, HNO3) was purchased from BDH Chemicals, 3-octanone (ACS grade 96% or higher) from EMD Millipore Corp, 1-octanol (laboratory grade) from Ward's Science, and ethanol (99.5% or higher, 200 proof) from EMD. All were used as received. Deionized (DI)H2O was obtained from an ELGA LabWater Purelab Flex ultrapure laboratory water purification system operated at 18.2 MΩcm at 25°C.

[0107] I purchased bismuth-207 from Eckert & Ziegler Isotope Products (Valencia, CA) as a Bi(NO3)3 solution with approximately 0.24 μCi per 1 mL and a total bismuth concentration of approximately 48 μM in 4 M HNO3.

[0108] method Quantitative analysis of Bi was performed using inductively coupled plasma mass spectrometry (ICP-MS) with a Thermo Fisher Scientific iCAP RQ mass spectrometer. 207 Semi-quantitative analysis of Bi and 211 Quantitative analysis of At was performed with a relative efficiency of 20.0% and an effective detection volume of approximately 115 cm³. 3 The analysis was performed via gamma (γ) ray spectroscopy using an InSpector® 2000 digital signal analyzer (DSA, Canberra Industries Inc. Meriden, CT) in conjunction with a calibrated Canberra Model GC2020 high-purity germanium detector (HPGe) and Genie-2000 software. The detector has an energy resolution of 1.0 keV at 122 keV and 1.98 keV at 1300 keV. Relevant nuclear data were obtained from Browne and Firestone. All calibrations were traceable to the National Institute of Standards and Instruments (NIST) and purchased from Eckert & Ziegler Isotope Products. 152 This was determined using a standard gamma-ray source from Europe.207 Bi was directly tracked using 1064 keV gamma rays. 211 At was directly tracked using X-rays at 76.9 keV, 79.9 keV, 89.8 keV, and 92.3 keV, as well as gamma rays at 687 keV. Impurities, 66 / 67 Ga was identified by half-life analysis (see SI), and 66 For Ga, gamma rays at 833 keV and 1039 keV, and 67 Ga was directly tracked using 185 keV and 300 keV gamma rays.

[0109] AT-211 manufacturing Astatine-211 was subjected to a natural Bi metal target (isotope-pure) for 9-10 hours using the K150 cyclotron at Texas A&M with an average beam current of 2.4-3.2 pμA. 209 Via a 28.8 MeV α particle collision (approximately 0.9 Burn cross-section)[7] of Bi (metal purity 99.997% or higher, purchased from Goodfellow) 209 Bi(α,2n) 211 The target was fabricated by an At nuclear reaction in two separate operations. The Bi metal target, with a mass of approximately 9.4 g or 1.0 g, was a racetrack-type ellipse (6.985 × 1.27 cm), with an estimated thickness of 950 μm or 100 μm, covered at one end by a semicircle (radius 0.635 cm), and housed in an aluminum frame (6061 Al alloy, 95% Al) in contact with a support block cooled by recirculated water cooled to 15°C. The target was held at a 10° angle from the beam to maximize target coverage while minimizing beam loss in the Al housing. The impact target was dissolved in either 11.2 M or 8 M HNO3, with a final HNO3 concentration of approximately 6 M. This solution was then sampled, and the results at the end of the impact were measured. 211 The yield of At was determined. 211 At and 207 Bi was handled in smaller quantities, in highly radioactive laboratories equipped with facilities for the proper handling of radioactive materials, in accordance with the ALARA principle, and radioactive biosafety cabinets were employed.

[0110] Distribution A series of extractions from various concentrations of HNO3 into several organic solvents were investigated. First, using simple straight-chain alcohols, 1-octanol and 1-decanol, from 1 - 3 M HNO3 211 At was extracted and shown in Figure 1. The extraction of At into 1-octanol 211 produced distribution ratio (D) values of approximately 37.9 ± 2.3, 42.0 ± 2.2, and 38.9 ± 2.1, respectively, at 1, 2, and 3 M concentrations of HNO3. Thus, the maximum extraction occurs around 2 M HNO3. In contrast, 207 the D values of Bi into 1-octanol were below 0.05 for all three acidities, which 207 is consistent with the amount of Bi being below the detection limit in the organic phase while all the activity present in the aqueous phase. Increasing the aliphatic chain length from C8 to C 10 results in 211 an adverse effect on the extraction of At, with D values of 12.3 ± 0.8 at 1 M HNO3, 8.4 ± 0.4 at 2 M HNO3, and 4.6 ± 0.2 at 3 M HNO3, corresponding to approximately 3, 5, and 9-fold decreases in extractability, respectively. Furthermore, the maximum extraction into 1-decanol appears to occur below 1 M HNO3, and the decrease in D value is linear when the HNO3 concentration increases from 1 to 3 M. While the exact mechanism of metal extraction with HNO3 is still unknown, the more nonpolar nature of 1-decanol appears to suppress the extraction. This could result from the need to maintain charge balance and the co-extraction of nitrate counter anions into the organic phase with the cationic At species. Assuming the At(III)AtO + molecular cation as the extracted species, the following equilibrium explains the extraction.

[0111]

Equation

[0112] To further test this, less polar solvents, diisopropyl ether and more polar solvent, methyl isobutyl ketone were investigated. 211The extraction of At into diisopropyl ether was in the range of 1-decanol, 207 Bi remained in the aqueous phase (D value ≤ 0.05). In the methyl isobutyl ketone system 211 At showed significantly different behavior compared to other solvent systems studied and exhibited strong HNO3 dependence. The extraction of At into methyl isobutyl ketone was slightly higher than that into 1-octanol at 1 M HNO3. On the other hand, when the HNO3 concentration was increased to 2 and 3 M, the D values increased by approximately 1.7-fold and 2.4-fold, respectively. On the other hand, 211 Bi showed behavior similar to other systems studied and had very low D values, ≤ 0.05. The second ketone, 3-octanone, which has a similar polarity to 1-octanol, was then tested to determine whether the solvation effect of the more polar methyl isobutyl ketone was the driving force for extraction or whether the carbonyl functional group of the ketone played a major role. In methyl isobutyl ketone, the extraction of At into 3-octanone was found to be similar to that into 1-octanol at 1 M HNO3. On the other hand, when the HNO3 concentration was increased to 2 and 3 M, the D values increased by approximately 1.2-fold and 1.8-fold, respectively. Furthermore, 207 Bi remained in the aqueous phase (D value ≤ 0.05). The enhanced extraction of AtO by ketones compared to alcohols was also demonstrated using DFT calculations, and the binding free energy of acetone was shown to be 4.6 kcal / mol stronger than that of isopropyl alcohol. 211 The extraction of At into 3-octanone was found to be similar to that into 1-octanol at 1 M HNO3. On the other hand, when the HNO3 concentration was increased to 2 and 3 M, the D values increased by approximately 1.2-fold and 1.8-fold, respectively. Furthermore, 207 Bi remained in the aqueous phase (D value ≤ 0.05). The enhanced extraction of AtO by ketones compared to alcohols was also demonstrated using DFT calculations, and the binding free energy of acetone was shown to be 4.6 kcal / mol stronger than that of isopropyl alcohol. + The extraction of At by ketones compared to alcohols was also demonstrated using DFT calculations, and the binding free energy of acetone was shown to be 4.6 kcal / mol stronger than that of isopropyl alcohol. -1 The overall behavior of the extraction of At in the 3-octanone and methyl isobutyl ketone systems was similar,

[0113] showing a linear relationship between the D value of At and the initial HNO3 concentration in the aqueous phase of 1 - 3 M HNO3. On the other hand, the slope of the methyl isobutyl ketone system was approximately 50% steeper than that of the 3-octanone system. As a function of HNO3 concentration, the extraction of At into methyl isobutyl ketone and 3-octanone 211 The overall behavior of the extraction of At in the 3-octanone and methyl isobutyl ketone systems was similar, 211 showing a linear relationship between the D value of At and the initial HNO3 concentration in the aqueous phase of 1 - 3 M HNO3. On the other hand, the slope of the methyl isobutyl ketone system was approximately 50% steeper than that of the 3-octanone system. As a function of HNO3 concentration, the extraction of At into methyl isobutyl ketone and 3-octanone 211The direct correlation of the D value of At may indicate an interaction between the ketone and the At metal center. Currently, the characteristics of such an interaction are not fully understood. Density functional calculations suggest that AtO + The empty π * Orbitals and acetone's "sp 2 AtO exhibits a strong donor-acceptor interaction between lone electron pairs. + NBO analysis of isopropanol is performed using its sp 3 O lone pair electrons, AtO + _Acetone sp 2 O has 0.11 fewer electrons than lone electron pair orbitals in AtO + This indicates that it provides to the corresponding AtO + and isopropyl alcohol "sp 3 The interaction of the O lone pair electrons is 4.6 kcal / mol stronger, while the solvent-corrected Gibbs free energy of the bond is AtO + AtO is better than isopropanol + Acetone still has a higher value at 2.1 kcal / mol. Therefore, the ketone is AtO + This exhibits a strong bond, leading to better extraction. At the H2O-organic interface, the organic molecule will have its polar end (oxygen) in or within the H2O layer. + and NO3 - Since it can be a solvent separated in the H2O layer, AtO + The initial interactions of these species regarding extraction involve the interaction of oxygen with organic molecules. + It is likely a combination of AtO. + The movement of NO3 into the organic layer is inevitable. - It will likely need to be accompanied by something else.

[0114] Extraction chromatography Pore ​​volume 0.7 mLg -1Amberchrom® CG300M porous beads and a slurry with a particle size of 50-100 μm in 20% ethanol were purchased from Sigma-Aldrich. Amberchrom® CG300M is a styrene-divinylbenzene copolymer that does not have functional groups on the benzene ring. Before use, the beads were dried at 80°C for a minimum of 24 hours to remove all solvent from the pores. Subsequently, the beads were impregnated with either 1-octanol or 3-octanone by immersing them in an organic solvent for at least 24 hours. Thermogravimetric analysis (TGA) was performed on the impregnated resin as well as the dried resin using a TA Instruments TGA 5500 under N2 flow at a heating rate of 10°C per minute. The impregnated resin was then packed into 2 mL Kontes® Flex-Columns with a bed volume (BV) of 0.5 mL and an inner diameter (ID) of 0.7 cm. To prevent the solvent from evaporating from the pores, excess organic solvent was retained in the column on a resin-impregnated bed. Immediately before extraction chromatography, the excess solvent was drained from the column.

[0115] The general chromatography procedure is as follows: in 2-6 M HNO3 211 0.5–5 mL of packing solution spiked with At (13 ± 1.3 μCi to 9.8 ± 0.98 mCi) was passed through the column in 0.5 mL aliquots, followed by 0.5 mL aliquots of the next four 2 M HNO3 solutions, then 0.5 mL aliquots of H2O, and finally 0.5 mL aliquots of three to five ethanol solutions. Elution of each fraction was accelerated by manually applying pressure to the top of the column using a syringe. In all cases, the fractions were collected in 0.5 mL portions and analyzed by gamma-ray spectroscopy. Following the general chromatography procedure, total organic carbon (TOC) analysis using a Shimadzu TOC-VWP analyzer was performed on the fractions eluted from a column packed with 3-octanone-impregnated resin (BV approximately 0.5 mL). However, no radionuclides were found.

[0116] Column characterization The loading of Amberchrom® CG300M resin impregnated with either 1-octanol or 3-octanone was determined by TGA and is shown in Figure 2. The dry, unimpregnated resin showed only a very small mass loss of 2.44% even when heated to 200°C, indicating only surface H2O adsorbed from the atmosphere. This low mass percentage from water is not surprising, as Amberchrom® CG300M is inherently hydrophobic and its phenyl functional groups are suspended within the pore space. The impregnated resin, on the other hand, exhibited considerably higher mass loss at 200°C: 70.2% for 1-octanol and 65.5% for 3-octanone. This indicates that the pores were filled with an organic solvent. However, due to their relatively low boiling point and high vapor pressure (see Table 1), lower temperatures are required to remove the solvent, and the beads must remain submerged in the solvent until immediately before use.

[0117] [Table 1]

[0118] To determine whether organic solvents leached from the pores during the chromatography process, total organic carbon analysis (TOC) was performed on the fractions of 6M HNO3, 2M HNO3, and H2O eluted by continuous extraction chromatography using beads impregnated with 3-octanone to achieve a BV of 0.5 mL. Figure 3 shows the amount of 3-octanone in each fraction and the leaching ratio relative to the bead density. The density of the 3-octanone-impregnated beads was calculated as 0.90 ± 0.05 g / mL as follows. The impregnated beads were separated from the excess 3-octanone solvent by centrifugation using a Costar® Spin-X® 0.45 μm cellulose acetate centrifugal tube filter with mini-centrifugation, and their mass was measured. Subsequently, a known volume of 3-octanone was added to the beads, and the volume displacement was measured and expressed by the following equation.

[0119]

number

[0120] Small amounts of 3-octanone were observed in the first two fractions, totaling 1.4% and 0.9% respectively, while the subsequent fraction was below baseline. The initial leaching of 3-octanone in the first two fractions of 6M HNO3 may be due to residual solvent in the inter-bead spaces rather than solvent adsorbed in the pores. This indicates that the leached organic solvent was hardly removed from the resin pores during the extraction chromatography process. 211 There is almost no bleeding of At, which is mainly due to the absorption into the impregnation solvent. 211 Extraction of At and extracted 211 The presence of at in solvents indicates that it remains in the pores. Other extractive chromatography systems based on silica scaffolding show a higher tendency for organic phase leaching and require additional multi-component solvent systems to improve the hydrophobic properties of the stationary phase.

[0121] Extraction chromatography 211 For At to be used in a pharmaceutical environment, it needs to be purified from both non-radioactive natural Bi and any radiochemical contaminants generated during its manufacture. As mentioned above, 211 At's short half-life (t 1 / 2 Approximately 7.2 hours is required to achieve separation from the host matrix, in this case, metal Bi, and rapid chemistry is needed. First, a small spike (approximately 13 μCi) of Run 1 is added to a 0.5 mL BV 1-octanol extraction chromatography system with the collision target solution dissolved in 2 M HNO3. 211 The test was conducted at At. As shown in the chromatogram in Figure 4, 211At was extracted to the column almost quantitatively (over 97%), while approximately 73% of Bi with a D value of ≤0.1 in 1-octanol and the majority of radiochemical contaminants were not retained, passing through the column and eluting in the packed fraction. Bi, along with the contaminant species, was further eluted in the 2M HNO3 wash, with the remainder recovered in the first fraction of the wash. It should be noted that no attempt was made to adjust the recovery of the fractions to match the packing solution front. That is, the packing solution was added to the top of the column, and each eluted drop was recovered. Thus, the first 200–250 μL of solution corresponded to the solution remaining in the free volume of the column (40–50% of BV). This indicates that while Bi and radiochemical contaminants were found in the first washing fraction from which they were recovered, they were likely to migrate through the column without complete inhibition and remain exclusively in the original packing solution. None of these species were present in the three subsequent fractions of the 2M HNO3 wash. 211 At remained almost entirely in the column, with only about 5% eluting during the overall wash. Similar to the subsequent wash fractionation, only trace amounts of At were eluted during the H2O flush. 211 Only At was present, and no other target species were present. Therefore, we tried stripping the column with ethanol, and in doing so, the extracted 211 An attempt was made to dissolve the organic solvent containing At and to elute it. However, the packed 211 Only small fractions of At were eluted in all three stripping fractions, and the total elution yield was approximately 13%. 211 The majority of At (approximately 79%) remained attached to the porous beads, which was an unexpected result. While the elution yield was lower than desired, the recovered amount was... 211 The At product is of high purity, completely decontaminated with Bi and other radiochemical mixtures, and has a decontamination factor (DF) of 10. 5 That was all.

[0122] the current, 211 The exact mechanism of At adhesion to the resin is not clear, but the resin skeleton and AtO +There appears to be an interaction with it. Amberchrom® CG300M resin is based on polystyrene-divinylbenzene polymer. When used as a support for a thin film of extractant ligand adsorbed on the surface, such as in metal ion extraction chromatography, the backbone is considered inert to the target metal species. AtO on the resin + One reason for species retention is the defects in the polymer generated during resin production and AtO + It could be due to molecular interactions. 211 The hypothesis that At interacts with defects in the polymer chain suggests that, conversely, the bulk functionality of the resin, in the case of Amberchrom® CG300M, is related to the phenyl group, 211 A very small amount of At is retained. 211 Approximately 10 μCi of At is held by the resin, which is 2.4 × 10 -14 Converted to moles, it is orders of magnitude smaller than the number of phenyl groups present. Phenyl groups and 211 If a strong interaction occurs at At, the expected result is: 211 This would be a nearly quantitative retention of At. On the other hand, if some interaction with defects is occurring, these defects only need to represent a fairly small fraction of the resin, <<0.01% (mass / mass%).

[0123] Next, a second extraction chromatography system, impregnated with 3-octanone instead of 1-octanol, was subjected to a small spike (approximately 13 μCi) of Run 1, in which the collision target solution was dissolved in 2 M HNO3. 211 At (see Figure 5), the experiment was conducted. Using 3-octanone allowed for higher HNO3 concentrations than with 1-octanol. 211 It can offer several advantages, including demonstrating enhanced extraction of At and being biosafe. Similar to 1-octanol, 3-octanone does not extract Bi, has a D value of less than 0.1, and Bi remains in the packing solution and passes through the column. Radiochemical impurities also remain in the packing solution and pass through the column without interference. 211At was more strongly extracted by the 3-octanone system, with a leaching of over 99%, and the minimum leaching upon washing or flushing was less than 3%. 211 The elution yield of At increased to 37%, with nearly 22% eluted from the second strip fraction alone. Despite this increased yield, 211 The majority of At (59%) remained on the resin. It should also be noted that, despite the low yield, the purity of the product was remarkably high, with a DF of 10 5 That's all. Similar to the 1-octanol system, 211 A small amount of At, approximately 7.7 μCi or 1.8 × 10⁻⁶ -14 The fact that moles are retained on the resin is consistent with the hypothesis that defects in the polymer chains are the cause of retention.

[0124] Following the increase in elution yield with the 3-octanone system, the acidity of the packing solution was increased to 6M HNO3 (chromatogram shown in Figure 6), 211 Before scaling up the amount of At, we determined whether it was necessary to adjust the acidity of the dissolution. Similar to 2M HNO3 packing, 211 At was extracted (over 98%), while Bi and other contaminants were not retained in the column and moved through it with the packing solution. 211 The At elution characteristics were equivalent to those packed with 2M HNO3, with approximately 25% being lost in the second strip fraction, and 43% high purity (DF, 10) across all three strips. 5 (That's all.) 211 Most of the At remains on the resin, 53% (approximately 6.9 μCi or 1.6 × 10⁻⁶) -14 (mol), it appears that binding occurred at defect sites on the polymer. The elution yield is not very high, 211 The fact that At did not dissolve until stripping indicates that the dissolved impact target solution can be directly filled without any adjustments.

[0125] After that, the activity of the spikes was approximately 211The concentration of At was increased to 1 mCi, and the elution characteristics of the 3-octanone-impregnated resin were investigated as a function of nitric acid concentration. Figures 7-9 show the results of filling with 2, 4, and 5.7 M HNO3, respectively. 211 The chromatogram of At is shown.

[0126] In all three cases (see Table 2), as in previous studies, the data is placed on the column. 211 Initial packing of At was nearly quantitative, approximately 97%, while Bi and radiochemical impurities also passed through the column without obstruction. All residual impurities were removed by washing with 2M HNO3 and flushing with H2O. 211 The majority of At (71-77%) was subsequently eluted from the column by stripping, with 40-44% removed in the first strip fraction and 20-23% removed in the second strip fraction. 13 μCi 211 One major difference from chromatograms using only At is, 211 Increasing the amount of At resulted in the resin filling more than the 50-59% observed in previous studies. 211 A smaller proportion of At was retained, only 19-24%. It should be noted that in these chromatograms, an attempt to match the fraction recovery to the solvent front was made by adjusting the recovery to approximately 250 μL. 207 Bi and 66 / 67 This appears to be a slight overestimation, as Ga was confirmed in the dead volume fraction.

[0127] Table 2 shows the spikes (approximately 1.0 mCi) from 399 μL of Run 2, in which the impact target was dissolved using a 3-octanone-impregnated Amberchrom® CG300M resin bed (0.5 mL BV, 7 mm ID × 13 mm height). 211 This is a comparative chromatography study of 1.5 mL aliquots of 2 M HNO3, 1.4 mL aliquots of 4 M HNO3, and 1.3 mL aliquots of 5.7 M HNO3, including At).

[0128] [Table 2]

[0129] *Notes: We assumed the dead volume to be half of the BV, but a small amount 207 Bi and 66 / 67 This appears to be an overestimation, as Ga was detected in the fraction. The data was corrected for decay to explain the difference in half-lives.

[0130] The separation was performed using Run 1 (approximately 6M HNO3) in which the target solution was dissolved. 211 The study was further scaled up using 5 mL aliquots of approximately 4.1 mCi of At. Figure 10 shows the elution characteristics of the scaled-up separation. 211 Similar to studies involving small amounts of At, the contaminant species were not retained by the column, and Bi and other undesirable species were washed away during packing. Even with very large masses, Bi was completely removed from the column in the washing fraction. More interestingly, in scaled-up separations... 211 This is the elution characteristic of At. Firstly, 211 Although more than 98% of At (approximately 4 mCi) was packed onto the column, no breakthrough was observed throughout the 5 mL packing volume. Secondly, between washing and flushing, 211 At had a bleed-through rate of only about 1%. Thirdly, 211 The majority of At was eluted in the first two stripping fractions, at 32% and 61% respectively, in the packed fraction. 211 At represents 95%, 10 5 The above is the DF. Again, it should be noted that no attempt has been made to adjust the fractional recovery to correspond to the packed solution front for this chromatogram. Therefore, the first 40-50% of the solution in each fraction is the residue solution from the previous fraction, held in the free volume of the column. The subsequent three strip fractions are: 211 It contained the minimum amount of At, which was 1%, 0.3%, and 0.1% or less, respectively. Ultimately, the resin was 211 Only a very small amount of At, less than 2%, is retained, and 82 μCi (approximately 1.9 × 10⁻⁶) is used. -13 It represents moles.

[0131] Ultimately, 211 The amount of At was increased to approximately 9.8 mCi, as shown in Figure 11. 211 Following the trend observed in the separation of At at 4.1 mCi, Bi and other radiochemical contaminants remain in the supernatant, while 211 At was strongly retained by the column with approximately 95% packing. 211 Only a very small amount (less than 1%) of At bleed-through was observed during washing and flushing, and it did not elute into the strip; the majority, approximately 71%, was recovered in the first stripping fraction. The continuous strip fraction included: 211 At accounted for approximately 16%, 3%, 1.2%, and less than 1%. DF was recovered on the strip. 211 At all, it remains high at 10 5 It was excessive. The larger proportion in the first fraction of the strip is due to the fact that the recovery of the fraction was adjusted to correspond to the free column volume. Again, 211 A small amount of At, approximately 2%, remained attached to the resin. 211 At's behavior is approximately 4.1 mCi (9.4 × 10⁻⁶). -12 From mol) 9.8 mCi (2.3 × 10 -11 When the quantity is increased to ), it remains very similar, even though the total quantity is more than double (2.4 times), 211 The actual increase in the amount of At is very small, 1.4 × 10⁻⁶ ‐11 It remains the same. This is due to other components of the chemical system, specifically 3-octanone (2.3 × 10⁻¹⁰). ‐3 A large, far excessive amount (in moles) remains, approximately 9 orders of magnitude. With this in mind, the separation system investigated was: 211 It should be able to cope with a further increase in At. 211 At is expected to be very suitable for impact targets, with a production scale of 20-100 mCi.

[0132] The solution was extracted mainly with resin impregnated with 3-octanone, eluted mainly with ethanol strips, and mainly in HNO3. 211The speciation of At has never been experimentally determined because the small amount of At present due to its short half-life hinders the application of traditional spectroscopic techniques. At(III) is AtO + As such, it is the dominant species in aqueous solutions. AtO + The empty π * Orbitals and ketones' "sp" 2 The strong donor-acceptor interaction between the lone electron pairs of O was calculated, and the AtO from HNO3 into 3-octanone was also calculated. + It is considered a power source for the efficient extraction of AtO + It is likely the dominant species in ethanol strips.

[0133] The entire process, from the addition of the first 0.5 mL packed aliquot to the elution of the fifth and final strip fractions, was completed in less than 20 minutes, despite the slow nature of manual eluent addition and fraction collection. Assuming the solution was supplied to the column using a pump and set to an appropriate rate of 2 mL / min, 211 The process of recovering more than 95% of At would take less than 5 minutes. As mentioned above, AtO + The reason for the affinity between the resin and the substance is currently unknown, which prevents a detailed explanation for why the scaled-up separation yield is much higher than its smaller counterpart. However, given the assumption that an interaction is occurring with defects in the resin, it is not unreasonable to conclude that in the scaled-up separation, all exposed defect sites on the resin have been saturated. If the sites are saturated, 211 Most of At was extracted into a solvent that filled the pores, and eluted by dissolving 3-octanone in an ethanol strip. High purity was obtained directly from nitric acid in nearly quantitative yield. 211 This process of recovering At represents a significant advance in At separation.

Claims

1. (a) A step of contacting a composition containing astatine and bismuth with nitric acid to form a first solution containing astatine, bismuth and nitric acid. (b) A step of contacting the resin with the first solution to separate astatine from the first solution and to distribute it into the resin, (c) A step of eluting astatine from the resin, Methods that include...

2. The method according to claim 1, wherein the resin is impregnated with a solvent.

3. The method according to claim 2, wherein the solvent includes an organic solvent.

4. The method according to claim 3, wherein the organic solvent is polar.

5. The organic solvent is optionally substituted with C １ ~C １８ The method according to claim 3, comprising an alkyl group.

6. The method according to claim 5, wherein the organic solvent contains a carbonyl.

7. The method according to claim 5, wherein the organic solvent comprises an aldehyde, ketone, ester, amide, carbonate, carboxylate, or carbamate.

8. The aforementioned organic solvent is formula C １ ~C ６ Alkyl-C(O)-C １ ~C ６ It is alkyl, C １ ~C ６ The method according to claim 5, wherein each hydrogen atom of the alkyl group is optionally substituted.

9. The method according to claim 3, wherein the organic solvent is octanone.

10. The method according to claim 3, wherein the organic solvent is 3-octanone.

11. where the organic solvent is C １ to C １８ alkanol, the method according to claim 3.

12. The method according to any one of claims 3 to 11, wherein the astatine has a D-value partition coefficient of at least 20 in the organic solvent.

13. The method according to any one of claims 3 to 11, wherein the astatine has a D-value partition coefficient of at least 40 in the organic solvent.

14. The method according to any one of claims 3 to 11, wherein the astatine has a D-value partition coefficient of at least 60 in the organic solvent.

15. The method according to any one of claims 3 to 11, wherein the astatine has a D-value partition coefficient of at least 80 in the organic solvent.

16. The method according to any one of claims 1 to 11, wherein the resin is an inert resin.

17. The method according to any one of claims 1 to 11, wherein the resin is a polymer resin, a zeolite, a molecular sieve, or porous glass beads.

18. The method according to any one of claims 1 to 11, wherein the resin comprises a styrene-divinylbenzene copolymer.

19. The method according to claim 18, wherein the benzene does not contain a functional group.

20. The aforementioned astatine, ２１１ The method according to any one of claims 1 to 11, wherein A is the method.

21. The aforementioned astatine, ２０９ The method according to any one of claims 1 to 11, wherein A is the method.

22. The method according to any one of claims 1 to 11, wherein the bismuth is not distributed into the resin.

23. The method according to any one of claims 1 to 11, wherein the nitric acid in the first solution is concentrated at a concentration of about 1 M to about 10 M.

24. The method according to any one of claims 1 to 11, wherein the nitric acid in the first solution is concentrated at a concentration of about 1 M to about 8 M.

25. The method according to any one of claims 1 to 11, wherein the nitric acid in the first solution is concentrated at a concentration of about 2 M to about 8 M.

26. The method according to any one of claims 1 to 11, further comprising the step of washing the resin after step (b).

27. The method according to claim 26, wherein the cleaning step is carried out by passing an aqueous solution through the resin.

28. The method according to claim 27, wherein the aqueous solution contains an acid.

29. The method according to claim 28, wherein the acid is nitric acid, hydrobromic acid, hydrochloric acid, sulfuric acid, or perchloric acid.

30. The method according to claim 28 or 29, wherein the concentration of the acid is about 1 M to about 10 M.

31. The method according to any one of claims 1 to 11 or 26 to 30, for recovering 85% or more of astatine from a mixture.

32. The method according to any one of claims 1 to 11 or 26 to 30, for recovering 90% or more of astatine from a mixture.

33. The method according to any one of claims 1 to 11 or 26 to 30, for recovering 95% or more of astatine from a mixture.

34. The method according to any one of claims 1 to 11 or 26 to 30, wherein the astatine has a purity of 90% or more after step (c).

35. The method according to any one of claims 1 to 11 or 26 to 30, wherein the astatine has a purity of 95% or more after step (c).

36. The method according to any one of claims 1 to 11 or 26 to 30, wherein the astatine has a purity of 99% or more after step (c).

37. The method according to any one of claims 1 to 11 or 26 to 30, wherein the elution step is carried out by contacting the resin with a second organic solvent.

38. The second organic solvent is acetone or C １ ~C １８ The method according to claim 37, comprising alkanol.

39. The method according to claim 38, wherein the second organic solvent contains ethanol.

40. The method according to claim 37, wherein the second organic solvent can be miscible in the first organic solvent.

41. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than approximately one hour.

42. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than approximately 30 minutes.

43. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than approximately 15 minutes.

44. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than approximately 10 minutes.

45. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than 20% of the half-life of astatine.

46. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than approximately 15% of the half-life of astatine.

47. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out in less than 10% of the half-life of astatine.

48. The method according to any one of claims 1 to 11, wherein steps (a), (b), and (c) are carried out at a rate of less than 5% of the half-life of astatine.

49. The method according to any one of claims 1 to 11, further comprising the step of preparing the resin before step (b).

50. The method according to claim 49, wherein the step of preparing the resin includes a step of contacting the resin with an organic solvent.

51. The method according to any one of claims 1 to 11, further comprising the step of labeling the therapeutic agent with the eluted astatine.

52. A to O ＋ X ‐ (X ‐ A composition containing (where is a counterion).

53. X ‐ The composition according to claim 52, wherein the composition is a nitrate, halide, or perchlorate.

54. X ‐ The composition according to claim 53, wherein the composition is a nitrate.

55. X ‐ The composition according to claim 53, wherein the composition is perchlorate.

56. X ‐ The composition according to claim 53, wherein the composition is a halide.

57. The composition according to claim 56, wherein the halide is a chloride.

58. The composition according to any one of claims 52 to 57, which is compounded with an organic solvent.

59. The organic solvent is optionally substituted with C １ ~C １８ The composition according to claim 58, comprising an alkyl group.

60. The composition according to claim 58, wherein the organic solvent contains a carbonyl.

61. The composition according to claim 58, wherein the organic solvent comprises an aldehyde, ketone, ester, amide, carbonate, carboxylate, or carbamate.

62. The aforementioned organic solvent is formula C １ ~C ６ Alkyl-C(O)-C １ ~C ６ It is alkyl, C １ ~C ６ The composition according to claim 58, wherein each hydrogen atom of the alkyl group is optionally substituted.

63. The composition according to claim 58, wherein the organic solvent is octanone.

64. The composition according to claim 58, wherein the organic solvent is 3-octanone.

65. The aforementioned astatine, ２１１ The composition according to any one of claims 52 to 64, wherein the composition is At.

66. The aforementioned astatine, ２０９ The composition according to any one of claims 52 to 64, wherein the composition is At.

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