Prostate specific membrane antigen (psma) ligands

Patent metadata

Field	Value
Publication number	US-2025312496-A1
Application number	US-202318866055-A
Country	US
Kind code	A1
Filing date	May 16, 2023
Priority date	May 17, 2022
Publication date	Oct 9, 2025
Grant date	—

Abstract

The present invention generally relates to the field of radiopharmaceuticals and their use in nuclear medicine as tracers, imaging agents and for the treatment of various disease states of PSMA-expressing cancers, especially prostate cancer, and metastases thereof. In particular, the present invention relates to a PSMA binding ligand or a pharmaceutically acceptable salt or solvate thereof as well as to the use of said PSMA binding ligand, the PSMA binding ligand comprising a PSMA binding motif Q and a chelator residue A linked via at least one linker L AQ comprising at least one, optionally N-alkylated, neutral amino acid X i .

First claim

1 - 17 . (canceled)

18 . A PSMA binding ligand or a pharmaceutically acceptable salt or solvate thereof comprising a PSMA binding motif Q and a chelator residue A, linked via at least one linker L AQ comprising at least one neutral amino acid X 1 ,
wherein X 1 is selected from the group consisting of Gly, Ala, βAla, Phe, amino hexanoic acid (—NH—(CH 2 ) 5 —C(═O)—) and amino acids comprising at least one —(CH 2 —CH 2 —O)— group between the N-terminus and the C-terminus, more preferably wherein X 1 is selected from the group consisting of Gly, Ala, βAla, Phe and amino acid residues having the structure —NH—CH 2 —CH 2 —O—(CH 2 —CH 2 —O) x1 —(CH 2 ) y1 —C(═O)— with x1 being an integer in the range of from 0 to 15, and y1 being 1 or 2.

19 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the PSMA binding ligand has the structure (I):

20 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the PSMA binding motif Q has the structure:

wherein:
R 1 is H or —CH 3 , preferably H, and
R 2 , R 3 and R 4 are independently of each other, selected from the group consisting of —CO 2 H, —SO 2 H, —SO 3 H, —OSO 3 H, —PO 2 H, —PO 3 H and —OPO 3 H 2 .

21 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof,
wherein A is a chelator residue derived from a chelator selected from the group consisting of 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid (=DOTA), N,N″-bis [2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N″-diacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid (=NOTA), 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid, (NODAGA), 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)pentanedioic acid (DOTAGA), 1,4,7-riazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane phosphinic acid (TRAP), 1,4,7-triazacyclononane-1-[methyl (2-carboxyethyl)phosphinic acid]-4,7-bis [methyl (2-hydroxymethyl)phosphinic acid] (NOPO), 3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1 (15), 11,13-triene-3,6,9-triacetic acid (=PCTA), N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-arninopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide (DFO), Diethylenetriaminepentaacetic acid (DTPA), Trans-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-DTPA), 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid (oxo-Do3A) p-isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), 1-(p-isothiocyanatobenzyl)-3-methyl-DTPA (1 B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1 M3B) and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA).

22 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein A is a chelator residue having a structure selected from the group consisting of:

preferably wherein A is a chelator residue having the structure

23 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the linker L AQ comprises at least one amino acid building block AS a , wherein AS a has the structure:

and
wherein Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl.

24 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the linker L AQ comprises at least one amino acid building block AS b , wherein AS b has the structure (b);

and
wherein Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl, preferably wherein Q 2 is

more preferably

25 . The PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof, wherein the PSMA binding ligand has the structure (Ia):

wherein:
R 1 is H or —CH 3 , preferably H,
R 2 , R 3 and R 4 are independently of each other, selected from the group consisting of —CO 2 H, —SO 2 H, —SO 3 H, —OSO 3 H, —PO 2 H, —PO 3 H and —OPO 3 H 2 ,
Q 1 is selected from the group consisting of alkylaryl, arylalkyl, aryl, alkylheteroaryl, heteroarylalkyl and heteroaryl,
Q 2 is selected from the group consisting of aryl, alkylaryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl and alkylheteroaryl,
q is an integer of from 0-3, and
n1 is an integer in the range of from 1 to 25.

26 . The PSMA binding ligand of claim 18 , wherein the linker L AQ comprises the building block (X 1 ) n1 , and wherein:
—X 1 is selected from the group consisting of Gly, Ala, βAla and Phe and n1 is in the range of from 2 to 20, preferably 3 to 15, more preferably, 3, 5, 10 or 15 or X 1 has the structure —NH—CH 2 —CH 2 —O—(CH 2 —CH 2 —O) x1 —(CH 2 ) y1 —C(═O)— and with integer x1 being in the range of from 0 to 15, and y1 being 1 or 2 and with n1 being 1, or X 1 has the structure —NH—(CH 2 ) 5 —C(═O)— and n1 is in the range of from 1 to 20, preferably 1 to 4, or X 1 is Tyr and n1 is in the range of from 2 to 20, preferably 3 to 15, more preferably, 3, 5, 10 or 15.

27 . A complex comprising:
(a) a radionuclide, and (b) the PSMA binding ligand of claim 18 or a pharmaceutically acceptable salt or solvate thereof.

28 . The complex of claim 27 , wherein the radionuclide is selected from the group consisting of 89 Zr, 44 Sc, 111 In, 90 Y, 66 Ga, 67 Ga, 68 Ga, 177 Lu, 99m Tc, 60 Cu, 61 Cu, 62 Cu, 64 Cu, 66 Cu, 67 Cu, 149 Tb, 152 Tb, 155 Tb, 153 Sm, 161 Tb, 153 Gd, 155 Gd, 157 Gd, 213 Bi, 225 Ac, 230 U, 223 Ra, 165 Er, 52 Fe, 59 Fe, and radionuclides of Pb (such as 203 Pb and 212 Pb, 211 Pb, 213 Pb, 214 Pb, 209 Pb, 198 Pb, 197 Pb), more preferably selected from the group consisting 90 Y, 68 Ga, 177 Lu, 225 Ac, and 213 Bi, more preferably, the radionuclide is 177 Lu or 225 Ac.

29 . A pharmaceutical composition comprising the PSMA binding ligand of claim 18 .

30 . A method for treating and/or preventing a PSMA expressing cancer and/or metastases thereof, comprising administering to a subject in need the complex of claim 27 .

31 . A method for treating and/or preventing PSMA expressing cancer and/or metastases thereof, in particular prostate cancer and/or metastases thereof, comprising administering to a subject in need the PSMA binding ligand or a pharmaceutically acceptable salt or solvate thereof of claim 18 .

32 . A method for diagnosing cancer and/or metastases thereof, preferably PSMA-expressing cancer and/or metastases thereof, in particular prostate cancer and/or metastases thereof, comprising using a diagnostic method comprising the complex of claim

Assignees

• Deutsches Krebsforschungszentrum Stiftung Des Oeffentlichen Rechts
• Univ Freiburg Albert Ludwigs

Inventors

• Eder Matthias
• Eder Ann-Christin
• Geis Nicolas

Classifications

• A61K51/0497 Primary

  conjugates with a carrier being an organic compounds · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0402 Primary

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

• A61K51/0482 Primary

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