Synthesis of the radiolabeled prostate-specific membrane antigen (PSMA) inhibitor [18F]DCFPyL

Patent metadata

Field	Value
Publication number	US-10947197-B2
Application number	US-201716308128-A
Country	US
Kind code	B2
Filing date	Jun 9, 2017
Priority date	Jun 10, 2016
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

Methods, and related compositions, for the improved synthesis of [ 18 F]DCFPyL are disclosed. Also provided are methods, and related compositions, for the use of [ 18 F]DCFPyL so produced.

First claim

That which is claimed:

1. A method of synthesizing 2-(3-{1-carboxy-5-[(6-[ 18 F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid ([ 18 F]DCFPyL), the method comprising:
(i) radiofluorinating a DCFPyL precursor comprising ester moiety protecting groups to form a radiofluorinated DCPFPyL precursor, wherein the precursor is (compound (3));

(ii) deprotecting the ester moiety protecting groups of the radiofluorinated DCPFPyL precursor of step (i) with phosphoric acid at a temperature of between 30° C. to 55° C. to form [ 18 F]DCFPyL in a reaction mixture; and
(iii) purifying the [ 18 F]DCFPyL from the reaction mixture of step (ii) to provide [18F]DCFPyL with a specific activity of at least 40 Ci/μmol.

2. The method of claim 1 , wherein step (i) and step (ii) are performed in one reactor.

3. 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.

4. The method of claim 3 , wherein the RFM further comprises a thermal heating cavity.

5. The method of claim 1 , wherein the synthesizing is automated by use of an automated radiochemistry synthesizer.

6. The method of claim 3 , wherein components of the RFM or the automated radiochemistry synthesizer are free of fluorine.

7. The method of claim 1 , wherein the DCFPyL precursor is synthesized according to

8. A composition comprising [ 18 F]DCFPyL and having a specific activity of at least 40 Ci/μmol.

9. A kit comprising the composition of claim 8 .

10. A method of imaging comprising (i) contacting cells, organs or tissues with a composition of claim 8 , and (ii) imaging the cells, organs or tissues.

11. A method of administering to a subject comprising (i) administering a composition of claim 8 to a subject, and (ii) imaging the subject.

12. A method of treating a subject comprising administering a composition of claim 8 to a subject in an amount effective to treat the subject.

13. The method of claim 1 , 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.

14. The method of claim 1 , 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 and 2-[3-[1-t-butylcarboxylate-(5-aminopentyl)]-uriedo]-di-t-butyl pentandioate.

15. The method of claim 1 , wherein the radiofluorinating a DCFPyL precursor is performed according to

16. 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.

17. The method of claim 16 , wherein the cartridge is an anion exchange chromatographic cartridge.

18. The method of claim 16 , wherein the radiofluorinating a DCFPyL precursor further comprises heating the combined solution of compound (3) and the dried [18F]fluoride ion.

19. The method of claim 18 , wherein the heating is done at a temperature between 30° C. to 70° C.

20. The method of claim 18 or 19 , wherein the heating time is for between 2 min to 10 min.

21. The method of claim 16 , wherein the eluate of step (c) comprising the [18F]fluoride ion is dried at a temperature of between 80° C. to 150° C.

22. The method of claim 16 or 21 , wherein the eluate of step (c) comprising the [18F]fluoride ion is dried under nitrogen flow.

23. The method of claim 16 or 21 , wherein the drying is performed for 50 seconds to 300 seconds.

24. The method of claim 16 , wherein CH3CN is added to the dried [18F]fluoride ion for further drying.

25. The method of claim 1 , wherein the temperature is maintained for 2 min to 10 min.

26. 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.

27. The method of claim 1 , wherein the purifying is performed by liquid chromatography.

28. The method of claim 27 , wherein the liquid chromatography involves at least one C18 column.

29. The method of claim 16 , wherein the cartridge is preconditioned by washing with water prior to trapping [18F]fluoride ion in the cartridge.

30. The composition of claim 8 , wherein the composition has a specific activity of at least 60 Ci/μmol.

31. The composition of claim 30 , wherein the composition has a specific activity of at least 100 Ci/μmol.

32. The composition of claim 31 , wherein the composition has a specific activity of at least 120 Ci/μmol.

33. The composition of claim 32 , wherein the composition has a specific activity of at least 150 Ci/μmol.

Assignees

• Univ Johns Hopkins

Inventors

• Ravert Hayden T
• Holt Daniel P
• Chen Ying
• Mease Ronnie C
• Fan Hong
• Pomper Martin G
• Dannals Robert F

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07D213/82 Primary

  in position 3 · CPC title

• A61K51/0497 Primary

  conjugates with a carrier being an organic compounds · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title