PSMA imaging agents

Patent metadata

Field	Value
Publication number	US-10894807-B2
Application number	US-201815975296-A
Country	US
Kind code	B2
Filing date	May 9, 2018
Priority date	Aug 22, 2011
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

Abstract

Compounds for targeting and agents for imaging, prostate-specific membrane antigen (PSMA) are disclosed. Methods of synthesizing compounds and imaging agents, as well as methods for imaging PSMA are also disclosed. The imaging agents disclosed are suitable for PET and SPECT imaging.

First claim

We claim:

1. A method comprising:
administering to a patient, a radio-labelled compound of Formula I:

and pharmaceutically acceptable salts and stereoisomers thereof,
wherein:
X 1 is CH or N;
X 2 is CH or N;
X 3 is (CH 2 ) 1-6 wherein at least one CH 2 is optionally replaced by at least one of CONH or aryl;
X 4 is selected from the group consisting of aryl, NH, CH 2 , and

X 5 is selected from the group consisting of CONH, C(O), (CH 2 ) 1-2 —C(O) and (CH 2 ) 1-2 —CONH;
X 6 is aryl or CH;
X 7 is CH or N;
X 8 is CH or N;
X 13 is (CH 2 ) 1-5 , where at least one CH 2 of (CH 2 ) 1-5 is replaced by a group selected from aryl, NH, CH 2 , and

R 1 is selected from the group consisting of alkyne, N 3 , NO 2 , —(CH 2 ) 1-20 —R 3 where at least one CH 2 of —(CH 2 ) 1-20 —R 3 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH 2 ) 1-20 —R 3 is optionally substituted with COOH or NO 2 ; and (—CH 2 —CH 2 —) 1-5 —NH 2 where at least one CH 2 of (—CH 2 —CH 2 —O—) 1-5 —NH 2 is optionally replaced by aryl or heteroaryl;
R 2 is selected from the group consisting of H, COOH or CH 2 —COOH; and
R 3 is selected from the group consisting of COOH, N 3 , alkyne, protecting group, halo and positron emitting isotope;
or
administering to a patient, a radio-labelled compound of Formula II:

and pharmaceutically acceptable salts and stereoisomers thereof,
wherein:
X 1 is CH or N;
X 2 is CH or N;
X 9 is (CH 2 ) 1-5 where at least one CH 2 is optionally replaced by NH,
X 10 is CH or N;
X 11 is selected from the group consisting of (CH 2 ), aryl, or heteroaryl, wherein at least one H of the aryl or heteroaryl is optionally replaced by NO 2 ,
X 12 is selected from the group consisting of O, CONH and (CH 2 ) 1-2 wherein at least one CH 2 is optionally replaced by NH;
R 2 is selected from the group consisting of H, COOH or CH 2 —COOH;
R 4 is selected from the group consisting of H, alkyne, N 3 , NO 2 , —(CH 2 ) 1-20 —R 8 where at least one CH 2 of —(CH 2 ) 1-20 —R 8 is optionally replaced by at least one of —O—, aryl, heteroaryl, NH or CONH and wherein at least one H of —(CH 2 ) 1-20 —R 8 is optionally substituted with COOH or NO 2 ;
R 8 is selected from the group consisting of H and —(CH 2 ) 1-10 —R 8 where at least one CH 2 of —(CH 2 ) 1-10 —R 8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH;
R 5 is selected from the group consisting of H and —(CH 2 ) 1-10 —R 8 where at least one CH 2 of —(CH 2 ) 1-10 R 8 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH; and
R 6 is selected from the group consisting of H and —(CH 2 ) 1-10 —R 8 where at least one CH 2 of —(CH 2 ) 1-10 —R 9 is optionally replaced by at least one of —O—, aryl, heteroaryl or CONH; and
R 8 is selected from the group consisting of COOH, N 3 , alkyne, protecting group, halo and positron emitting isotope;
or
administering to a patient a radio-labelled compound of Formula III:

and pharmaceutically acceptable salts and stereoisomers thereof,
wherein:
X 1 is CH or N;
X 13 is (CH 2 ) 1-5 wherein at least one CH 2 is optionally replaced by aryl;
R 2 is selected from the group consisting of H, COOH or CH 2 —COOH;
R 11 is selected from the group consisting of alkyne, N 3 , NO 2 , (CH 2 ) 1-10 —R 12 wherein at least one CH 2 is optionally replaced by at least one of CONH, aryl or heteroaryl; and
R 12 is selected from the group consisting of N 3 , alkyne, protecting group, halo and radioisotope;
scanning the patient using positron emission tomography or single photon emission computed tomography; and
imaging a tissue in the patient.

2. The method of claim 1 , where the tissue includes a PSMA expressing tissue in mammals.

3. The method of claim 1 , wherein in Formula I, X 1 and X 2 are N.

4. The method of claim 1 , wherein in Formula I, X 1 is CH.

5. The method of claim 1 , wherein in Formula I, R 2 is COOH or H.

6. The method of claim 1 , wherein in Formula I, X 6 is CH.

7. The method of claim 1 , wherein in Formula I, R 1 is —(CH 2 ) 1-10 —R 3 where at least one CH 2 of —(CH 2 ) 1-20 —R 3 is replaced by at least one of aryl, heteroaryl or CONH.

8. The method of claim 7 , wherein in Formula I, at least one CH 2 of —(CH 2 ) 1-10 —R 3 is replaced by aryl.

9. The method of claim 8 , wherein in Formula I, at least one CH 2 of —(CH 2 ) 1-10 —R 3 is replaced by a triazole.

10. The method of claim 1 , wherein in Formula I, X is CONH or (CH 2 ) 1-2 —CONH.

11. The method of claim 1 , wherein X 4 and X 13 are C 6 H 6 or (CH 2 ) 1-5 .

12. The method of claim 1 , wherein in Formula I, X 5 is C(O) and X 4 is (CH 2 ) 1-5 , wherein one CH 2 of (CH 2 ) 1-5 is replaced by NH.

13. The method of claim 1 , wherein in Formula I, X 5 is C(O), X 4 and X 13 are

and wherein X 8 is N.

14. The method of claim 1 , wherein in Formula I, X 5 is C(O), X 13 is

wherein X 8 is N and X 4 is (CH 2 ) 3 —NH.

15. The method of claim 1 , wherein in Formula I, X 3 is (CH 2 ) 1-6 .

16. The method of claim 1 , wherein in for X 3 in Formula I, at least one CH 2 of (CH 2 ) 1-6 is replaced by CONH.

17. The method of claim 1 , wherein in Formula I, X 3 is CH 2 .

18. The method of claim 1 , wherein for X 3 in Formula I, at least one CH 2 of (CH 2 ) 1-6 is replaced by aryl.

19. The method of claim 18 , wherein in Formula I, one CH 2 of (CH 2 ) 1-6 is replaced by CONH.

20. The method of claim 1 , wherein in Formula I, R 3 is the positron emitting isotope.

21. The method of claim 1 , wherein in Formula I, R 1 is selected from the group consisting of:

22. The method of claim 1 wherein the compound is:

and pharmaceutically acceptable salts and stereoisomers thereof, wherein R 10 is a radionuclide.

23. The method of claim 1 , wherein in Formula II,
X 1 is N;
X 2 is N,
R 2 is COOH; and
R 6 is H.

24. The method of claim 23 , wherein in Formula II, R 4 is H, R 6 is H and R 5 is —(CH 2 ) 1-10 —R 8 where at least one CH 2 of —(CH 2 ) 1-10 —R 8 is replaced by heteroaryl and at least one CH 2 is replaced by CONH.

25

Assignees

• Siemens Medical Solutions Usa Inc

Inventors

• Wang Eric
• Kolb Hartmuth C
• Szardenings Anna Katrin
• Liu Changhui
• Walsh Joseph C
• Chen Gang
• Sinha Anjana
• Kasi Dhanalakshmi
• Yu Chul
• Gangadharmath Umesh B
• Zhang Wei
• Zhao Tieming
• Mocharla Vani P

Classifications

• C07K5/06113

  Asp- or Asn-amino acid · CPC title

• C07D213/81

  Amides; Imides · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title