Claims for Patent: 11,851,407

Summary for Patent: 11,851,407

Title:	Synthesis of the radiolabeled prostate-specific membrane antigen (PSMA) inhibitor [18F]DCFPYL
Abstract:	Methods, and related compositions, for the improved synthesis of [18F]DCFPyL are disclosed. Also provided are methods, and related compositions, for the use of [18F]DCFPyL so produced.
Inventor(s):	Hayden T. Ravert, Daniel P. Holt, Ying Chen, Ronnie C. Mease, Hong Fan, Martin G. Pomper, Robert F. Dannals
Assignee:	Johns Hopkins University
Application Number:	US17/195,895
Patent Claims:	1. A method of synthesizing 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid [18F]DCFPyL), the method comprising: (i) radiofluorinating a DCFPyL precursor comprising ester moiety protecting groups to form a radiofluorinated DCPFPyL precursor; (ii) deprotecting the ester moiety protecting groups of the radiofluorinated DCPFPyL precursor of step (i) with phosphoric acid to form [18F]DCFPyL in a reaction mixture; and (iii) purifying the [18F]DCFPyL from the reaction mixture of step (ii) to provide [18F]DCFPyL. 2. The method of claim 1, wherein the protecting groups are selected from the group consisting of benzyl, p-methoxybenzyl, tertiary butyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl (TBDMS), and triphenylmethyl. 3. The method of claim 1, wherein step (i) and step (ii) are performed in one reactor. 4. The method of claim 1, wherein the synthesizing is automated by use of a radiofluorination module (RFM) comprising a heating block, two syringe pumps, a multi-port cap, and valved reagent addition vials. 5. The method of claim 4, wherein the RFM further comprises a thermal heating cavity. 6. The method of claim 4, wherein components of the RFM or the automated radiochemistry synthesizer are free of fluorine. 7. The method of claim 1, wherein the synthesizing is automated by use of an automated radiochemistry synthesizer. 8. The method of claim 1, wherein the DCFPyL precursor is 5-(((S)-6-(tert-butoxy)-5-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-6-oxohexyl)carbamoyl)-N,N,N-trimethylpyridin-2-aminium compound. 9. The method of claim 8, wherein the DCFPyL precursor is 5-(((S)-6-(tert-butoxy)-5-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-6-oxohexyl)carbamoyl)-N,N,N-trimethylpyridin-2-aminium trifluoromethanesulfonate. 10. The method of claim 8, wherein the DCFPyL precursor is 5-(((S)-6-(tert-butoxy)-5-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)-6-oxohexyl)carbamoyl)-N,N,N-trimethylpyridin-2-aminium trifluoroacetate. 11. The method of claim 9, wherein the DCFPyL precursor is synthesized according to 12. The method of claim 9, wherein the DCFPyL precursor is synthesized by a method comprising: coupling of N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)carbonyl)-pyridin-2-aminium trifluoromethanesulfonate and 2-{3-[1-t-butylcarboxylate-(5-aminopentyl)]-uriedo]-di-t-butyl pentandioate. 13. The method of claim 9, wherein the method further comprises synthesizing the DCFPyL precursor according to or by coupling of N,N,N-trimethyl-5-((2,3,5,6-tetrafluorophenoxy)carbonyl)-pyridin-2-aminium trifluoromethanesulfonate 2-[3-[1-t-butylcarboxylate-(5-aminopentyl)]-uriedo]-di-t-butyl pentandioate. 14. The method of claim 1, wherein the radiofluorinating a DCFPyL precursor is performed according to 15. The method of claim 1, wherein the radiofluorinating a DCFPyL precursor comprises: (a) trapping [18F]fluoride ion in a cartridge; (b) eluting the cartridge with a solution of tetrabutylammonium base salt to release the [18F]fluoride ion trapped in the cartridge; (c) drying the eluate comprising the [18F]fluoride ion to form dried [18F]fluoride ion; and (d) adding a solution of (compound (3)) to the dried [18F]fluoride ion. 16. A composition comprising [18F]DCFPyL produced by the method of claim 1, wherein the [18F]DCFPyL has a specific activity of at least 40 Ci/μmol. 17. A kit comprising the composition of claim 16. 18. A method of imaging comprising contacting cells, organs or tissues with a composition of claim 16. 19. A method of administering to a subject a composition of claim 16, and imaging the subject. 20. The composition of claim 16, wherein the composition has a specific activity of at least 60 Ci/mmol. 21. The composition of claim 20, wherein the composition has a specific activity of at least 100 Ci/mmol. 22. The composition of claim 21, wherein the composition has a specific activity of at least 120 Ci/mmol. 23. The composition of claim 22, wherein the composition has a specific activity of at least 150 Ci/mmol. 24. The method of claim 1, further comprising adjusting the pH of the reaction mixture of step (ii) after the deprotecting with phosphoric acid to a pH of between 2 to 2.5. 25. The method of claim 1, wherein the purifying is performed by liquid chromatography. 26. The method of claim 25, wherein the liquid chromatography involves at least one CI8 column. 27. A method of radiofluorinating a DCFPyL precursor, which comprises: (i) trapping [18F]fluoride ion in a cartridge; (ii) eluting the cartridge with a solution of tetrabutylammonium hydrogen carbonate (TBABC) to release the [18F]fluoride ion trapped in the cartridge, (iii) drying the eluate comprising the [18F]fluoride ion from step (ii); (iv) adding a solution of (compound (3)) to the [18F]fluoride ion from step (iii); and (v) heating the combined solution of step (iv). 28. The method of claim 27, wherein the heating of step (v) is performed at a temperature between 30° C. to 70° C. 29. The method of claim 27, wherein the heating of step (v) is performed for a period of time between 2 min to 10 min. 30. The method of claim 27, wherein the eluate of step (iii) comprising the [18F]fluoride ion is dried at a temperature of between 80° C. to 150° C. 31. The method of claim 27, wherein the eluate of step (iii) comprising the [18F]fluoride ion is dried under a nitrogen flow. 32. The method of claim 27, wherein the drying of step (iii) is performed for a period of time between 50 seconds to 300 seconds. 33. The method of claim 27, further comprising adding CH3CN to the eluate of step (iii) comprising the [18F]fluoride ion for further drying. 34. The method of claim 27, wherein the cartridge is preconditioned by washing with water prior to trapping [18F]fluoride ion in the cartridge.