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

Patent metadata

Field	Value
Publication number	US-12472272-B2
Application number	US-202017604703-A
Country	US
Kind code	B2
Filing date	Apr 16, 2020
Priority date	Apr 17, 2019
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

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).

First claim

What is claimed is:

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

Assignees

• Provincial Health Services Authority
• Univ British Columbia

Inventors

• Lin Kuo-Shyan
• Bénard François
• Kuo Hsiou-Ting
• Merkens Helen
• Zhang Zhengxing

Classifications

• A61K51/0482

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

• A61K51/048

  DTPA (diethylenetriamine tetraacetic acid) · CPC title

• A61K51/0478

  complexes from non-cyclic ligands, e.g. EDTA, MAG3 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0497 Primary

  conjugates with a carrier being an organic compounds · CPC title