IP Library › Granted Patent US 12,472,272
Granted Patent B2
US 12,472,272 · App. 17/604,703 · Granted Nov 18, 2025

Radiolabelled compounds for diagnosis or treatment of prostate-specific membrane antigen- expressing cancer

Inventors: Kuo-Shyan Lin (Richmond, CA); François Bénard (Vancouver, CA); Hsiou-Ting Kuo (Sherbrooke, CA); Helen Merkens (Burnaby, CA); Zhengxing Zhang (Vancouver, CA)
Assignees: PROVINCIAL HEALTH SERVICES AUTHORITY; THE UNIVERSITY OF BRITISH COLUMBIA
A61K51/0497A61K51/0478A61K51/048A61K51/0482A61P35/00
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Quick Facts
Patent No.
US 12,472,272
App. No.
17/604,703
Granted
Nov 18, 2025
Kind
B2
Abstract

This application relates to compounds of Formula I. R 1a , R 1b and R 1c is —CO 2 H, —SO 2 H, —SO 3 H, —SO 4 H, —PO 2 H, —PO 3 H or —PO 4 H. R 2 is a linker, e.g. butylene. R 3 is a linkage, e.g. —O—, —S—, —S(O)—, S(O) 2 —, —NHC(O)—, —C(O)NH—, or 1,2,3-triazole. R4 is —(CH 2 ) 0-3 CH(R 7 )(CH 2 ) 0-3 — wherein R 7 is —(CH 2 ) 5 CH 3 or certain aromatic fused-ring systems. R 5 and R 6 are hydrogen or methyl. Each Xaa 1 (if present) is an amino acid. R X is a radiolabeling group, e.g.: a radiometal chelator optionally bound by a radiometal; an aryl substituted with a radioisotope; a prosthetic group containing a trifluoroborate; or a prosthetic group containing a silicon-fluorine-acceptor moiety. The compounds may be useful for imaging prostate-specific membrane antigen (PSMA)-expressing tissues or for treating PSMA-expressing diseases (e.g. cancer).

Claims (63)

1 . A compound, wherein the compound has Formula I or is a salt or a solvate of Formula I:

wherein:

each of R 1a , R 1b and R 1c is independently —CO 2 H, —SO 2 H, —SO 3 H, —SO 4 H, —PO 2 H, —PO 3 H, or —PO 4 H;

R 2 is a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 20 alkylenyl or alkenylenyl, or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 20 heteroalkylenyl or heteroalkenylenyl;

R 3 is —O—, —S—, —S(O)—, —S(O) 2 —, —NHC(O)—, —C(O)NH—,

R 4 is —(CH 2 ) 0-3 CH(R 7 )(CH 2 ) 0-3 —, wherein R 7 is (CH 2 ) 5 CH 3 ,

each of R 5 and R 6 is independently hydrogen or methyl;

Xaa 1 is an amino acid of formula —N(R 8 )R 9 C(O)—, wherein each R 8 is independently hydrogen or methyl, and wherein each R 9 is independently: a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 1 -C 20 alkylenyl, alkenylenyl, or alkynylenyl; or a linear or branched, cyclic or acyclic, and/or aromatic or non-aromatic C 2 -C 20 heteroalkylenyl, heteroalkenylenyl, or heteroalkynylenyl; and

R X is a radiolabeling group independently selected from: a radiometal chelator optionally bound by a radiometal; an aryl substituted with a radioisotope; a prosthetic group containing a trifluoroborate; and a prosthetic group containing a silicon-fluorine-acceptor moiety.

2 . The compound of claim 1 , which is of Formula I-a or is a salt or solvate of Formula I-a

3 . The compound of claim 1 , which is of Formula I-b or is a salt or solvate of Formula I-b

4 . The compound of claim 1 , wherein R 7 is —(CH 2 ) 5 CH 3 ,

or

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

6 . The compound of claim 1 , wherein R 7 forms the side chain of an L-amino acid residue.

7 . The compound of claim 1 , wherein R 7 forms the side chain of a D-amino acid residue.

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

9 . The compound of claim 1 , wherein R 2 is a linear or branched C 1 -C 20 alkylenyl in which 0-5 carbons are replaced with N, S, and/or O heteroatoms.

10 . The compound of claim 1 , wherein R 2 is —(CH 2 ) 1-8 —.

11 . The compound of claim 1 , wherein R 2 is —(CH 2 ) 4 —.

12 . The compound of claim 1 , wherein R 3 is —NHC(O)— or —C(O)NH—.

13 . The compound of claim 1 , wherein R 5 is hydrogen.

14 . The compound of claim 1 , wherein R 6 is hydrogen.

15 . The compound of claim 1 , wherein each of R 1a , R 1b , and R 1c is —CO 2 H.

16 . The compound of claim 1 , wherein the compound is of Formula II or is a salt or solvate of Formula II

17 . The compound of claim 1 , wherein (Xaa 1 ) 0-4 is Xaa 1 .

18 . The compound of claim 1 , wherein each R 9 is independently: a linear or branched C 1 -C 18 alkylenyl in which 0-5 carbons are replaced with N, S, and/or O heteroatoms; or —CH(CH 2 R 10 )— wherein each R 10 is independently a C 5 -C 16 cyclic or multicylic system in which 0-5 carbons are replaced with N and optionally substituted with 0-5 hydroxy groups, and which is non-aromatic, partially aromatic or fully aromatic.

19 . The compound of claim 1 , wherein each Xaa 1 is an amino acid independently selected from a proteinogenic amino acid or an amino acid listed in Table 1, and R X forms an amide bond with Xaa 1 .

20 . The compound of claim 1 , wherein (Xaa 1 ) 0-4 is (Xaa 1 ) 2-4 in which each Xaa 1 is an amino acid independently selected from a proteinogenic amino acid or an amino acid listed in Table 1, and wherein the linkages between Xaa 1 groups and between R X and Xaa 1 are amide bonds.

21 . The compound of claim 1 , wherein (Xaa 1 ) 0-4 is absent.

22 . The compound of claim 1 , wherein R X is polyaminocarboxylate chelator attached through an amide bond.

23 . The compound of claim 1 , wherein R X is:

DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or a derivative thereof;

TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) or a derivative thereof;

SarAr (1-N-(4-Aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine) or a derivative thereof;

NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) or a derivative thereof;

TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or a derivative thereof;

HBED (N,N′-bis(2-hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid) or a derivative thereof;

2,3-HOPO (3-hydroxypyridin-2-one) or a derivative thereof;

PCTA (3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) or a derivative thereof;

DFO (desferrioxamine) or a derivative thereof;

DTPA (diethylenetriaminepentaacetic acid) or a derivative thereof;

OCTAPA (N,N′-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N′-diacetic acid) or a derivative thereof; or

H 2 -MACROPA (N,N′-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6) or a derivative thereof.

24 . The compound of claim 23 , wherein R X is DOTA.

25 . The compound of claim 1 , wherein R X is a chelator moiety in complex with radioisotope X wherein X is 64 Cu, 67 Cu, 90 Y, 111 In, 114m In, 117m Sn, 153 Sm, 149 Tb, 161 Tb, 177 Lu, 225 Ac, 213 Bi, 224 Ra, 212 Bi, 212 Pb, 227 Th, 223 Ra, 47 Sc, 186 Re, or 188 Re.

26 . The compound of claim 25 , wherein X is 177 Lu.

27 . The compound of claim 1 , wherein R X is a chelator moiety in complex with radioisotope X wherein X is 64 Cu, 68 Ga, 86 Y, 111 In, 94m Tc, 44 Sc, 89 Zr, or 99m Tc.

28 . The compound of claim 27 , wherein X is 68 Ga.

29 . The compound of claim 1 , wherein R X is an aryl substituted with a radioisotope.

30 . The compound of claim 29 , wherein the radioisotope is 131 I.

31 . The compound of claim 1 , wherein R X is a prosthetic group containing a trifluoroborate.

32 . The compound of claim 31 , wherein the prosthetic group is selected from Table 3 or 4.

33 . The compound of claim 31 , wherein the prosthetic group is

wherein each R is a branched or linear C 1 -C 5 alkyl.

34 . The compound of claim 1 , wherein R X is a prosthetic group containing a silicon-fluorine-acceptor moiety.

35 . The compound of claim 31 , wherein the prosthetic group comprises 18 F.

36 . A method of imaging a prostate-specific membrane antigen (PSMA)-expressing cancer in a subject, comprising administering to the subject in need of imaging an effective amount of a compound of claim 1 ; and imaging the PSMA-expressing cancer, wherein R X comprises or is complexed with an imaging radioisotope.

37 . A method of treating a prostate-specific membrane antigen (PSMA)-expressing cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 ; wherein R X comprises or is complexed with a therapeutic radioisotope.

38 . The method of claim 37 , wherein the PSMA-expressing cancer is 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, or sarcoma.

39 . The method of claim 36 , wherein the PSMA-expressing cancer is 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, or sarcoma.

40 . The compound of claim 1 of Formula I or a salt or a solvate of Formula I having the following chemical formula:

wherein R is

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 23, 2022
From: LIN, KUO-SHYAN; BÉNARD, FRANÇOIS; MERKENS, HELEN; ZHANG, ZHENGXING
To: PROVINCIAL HEALTH SERVICES AUTHORITY
Reel/Frame 059079/0381 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 23, 2022
From: KUO, HSIOU-TING
To: THE UNIVERSITY OF BRITISH COLUMBIA
Reel/Frame 059079/0411 →
Continuity (2)
Provisional Application 62835183 · Apr 17, 2019
Related Publication 20220233726A1 · Jul 28, 2022
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