Radiolabeled compounds targeting the prostate-specific membrane antigen

Patent metadata

Field	Value
Publication number	US-11504441-B2
Application number	US-202117371587-A
Country	US
Kind code	B2
Filing date	Jul 9, 2021
Priority date	Jun 21, 2019
Publication date	Nov 22, 2022
Grant date	Nov 22, 2022

Abstract

A compound comprising a prostate specific membrane antigen (PSMA)-targeting moiety of the following formula or of a salt or a solvate thereof. R0 is O or S. Each of R1a, R1b and R1c may be —CO2H, —SO2H, —SO3H, —PO2H, or —PO3H2, for example. R2 may be methylene or a derivative thereof, propylene or a derivative thereof, or a derivative of ethylene, optionally substituted. R3 is a linker. When the PSMA-targeting moiety is linked to a radiolabeling group, the compound may be used as an imaging agent or therapeutic agent for PSMA-expressing diseases/conditions.

First claim

The invention claimed is:

1. A compound of Formula II:

wherein:
R 0 is O;
R 1a , R 1b , and R 1c are each —CO 2 H;
R 2 is —CH 2 — or —(CH 2 ) 3 —;
R 3 is a linear C 4 alkylenyl;
—(Xaa 1 ) 1-4 N(R 6 )R 5 R 4 — is:

R 6 is H, methyl or ethyl;
R 7 is:

(Xaa 2 ) 0-4 is absent;
(Xaa 2 ) 1-4 is a tripeptide;
R 10 is:

optionally modified with one or more of halogen, —OCH 3 , —NH 2 , —NO 2 , —CN, —OH, or additional endocyclic ring nitrogen atoms, or combinations thereof;
R 11 is absent,

R 12 is I, Br, F, Cl, H, —OH, —OCH 3 , —NH 2 , —NO 2 , or —CH 3 ; and
R X is a radiometal chelator optionally bound to a radiometal, or a prosthetic group containing a trifluoroborate.

2. The compound of claim 1 , wherein R 6 is H.

3. The compound of claim 1 , wherein R 7 is:
R X —(Xaa 2 ) 0-4 or

4. The compound of claim 1 , wherein R 10 is

5. The compound of claim 1 , wherein:
R 11 is

and
R 12 is —OCH 3 or Cl.

6. The compound of claim 1 , wherein R X is DOTA, H 2 macropa, H 4 py4pa, or H 4 Pypa, each of which is optionally bound to a radiometal.

7. The compound of claim 3 , wherein R 10 is

8. The compound of claim 3 , wherein:
R 11 is

and
R 12 is —OCH 3 or Cl.

9. The compound of claim 7 , wherein:
R 11 is

and
R 12 is —OCH 3 or Cl.

10. The compound of claim 1 which is

and the compound is optionally bound to a radiometal.

11. The compound of claim 1 , wherein the radiometal is selected from the group consisting of 177 Lu, 111 In, 213 Bi, 68 Ga, 67 Ga, 203 Pb, 212 Pb, 44 Sc, 47 Sc, 90 Y, 86 Y, 225 Ac, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 165 Er, 212 Bi, 227 Th, 64 Cu and 67 Cu.

12. The compound of claim 10 , wherein the radiometal is selected from the group consisting of 177 Lu and 225 AC.

13. The compound of claim 1 , wherein R 7 is R X —(Xaa 2 ) 0-4 — and R X is DOTA, optionally chelated with 68 Ga, 177 Lu, or 225 Ac.

14. The compound of claim 1 , wherein R 7 is

(Xaa 2 ) 1-4 is a tripeptide, and each R X is independently —C(O)—(CH 2 ) 0-5 R 18 —(CH 2 ) 1-5 R 17 B 18 F 3 , wherein R 18 is

and R 17 B 18 F 3 is

and R 19 and R 20 are independently C 1 —c 5 linear or branched alkyl groups.

15. A method of treating a PSMA-expressing condition or disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

16. A method of treating a PSMA-expressing condition or disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 10 .

17. The method of claim 15 , wherein the PSMA-expressing condition or disease is a cancer selected from the group consisting of prostate cancer, renal cancer, breast cancer, thyroid cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, lung cancer, liver cancer, brain tumor, melanoma, neuroendocrine tumor, ovarian cancer, and sarcoma.

18. The method of claim 17 , wherein the PSMA-expressing condition or disease is prostate cancer.

19. A method of imaging PSMA-expressing tissues, comprising administering to a patient in need of such imaging an effective amount of a compound of claim 1 ; and imaging the tissues of the patient.

20. The method of claim 19 , wherein said imaging is performing PET or SPECT imaging.

Assignees

• Provincial Health Services Authority
• Univ British Columbia

Inventors

• Lin Kuo-Shyan
• Bénard François
• Kuo Hsiou-Ting
• Zhang Zhengxing
• Perrin David

Classifications

• A61K51/0402 Primary

  carboxylic acid carriers, fatty acids (amino acids A61K51/0406) · CPC title

• A61K51/088 Primary

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0482

  chelates from cyclic ligands, e.g. DOTA · CPC title

• C07B59/004

  Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium · CPC title