Psma targeting urea-based ligands for prostate cancer radiotherapy and imaging

Patent metadata

Field	Value
Publication number	US-2023201383-A1
Application number	US-202118000679-A
Country	US
Kind code	A1
Filing date	Jun 4, 2021
Priority date	Jun 4, 2020
Publication date	Jun 29, 2023
Grant date	—

Abstract

The present invention provides novel PSMA targeting urea-based ligands that binds to prostate-specific membrane antigen (PSMA) which is expressed 8-to-12-fold higher in prostate cancer cells when compared to healthy tissue. The PSMA targeting urea-based ligands comprises a chelating agent that may comprise a metal and a halogen radioisotope of fluorine, iodine, bromine or astatine. The invention further relates to a method for providing the PSMA targeting urea-based ligands of the invention, to precursors of the PSMA targeting urea-based ligands and to the PSMA targeting urea-based ligands use in radiotherapy, imaging and theranostic.

First claim

1 . A PSMA targeting ligand of formula (I)

wherein:
A is independently carboxylic acid, sulphonic acid, phosphonic acid, tetrazole or isoxazole;
L is selected from the group consisting of urea, thiourea, —NH—(C═O)—O—, —O—(C═O)—NH— or —CH 2 —(C═O)—CH 2 —;
K is selected from the group consisting of —(C═O)—NH—, —CH 2 —NH—(C═O)— or

wherein
p is independently an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6;
q is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6;
Y is selected from the group consisting of:

wherein
Q 1 is —C—R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl;
Q 2 is O, S or NH;
Hal is a nuclide or a radionuclide of the halogen group selected from the group consisting of isotopes and radioisotopes of fluorine, iodine, bromine or astatine;
M is a chelating agent, that can comprise a metal;
n is an integer selected from the group consisting of 1, 2, 3, 4, 5 and 6;
m is an integer selected from the group consisting of 0 and 1;
o is an integer selected from the group consisting of 0 and 1;
R 1 is —CH—CH 2 —Z or —CH—CH 2 —Y;
wherein Z is selected from the group consisting of:

and Y is selected from the group consisting of:

wherein
Q 1 is —C—R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl;
Q 2 is O, S or NH;
Hal is a nuclide or radionuclide of the halogen group selected from the group consisting of isotopes and radioisotopes of fluorine, iodine, bromine or astatine;
R 2 is —CH—CH 2 —Y or —CH 2 —X—;
wherein X is an aromatic monocyclic or polycyclic ring system having 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
and Y is selected from the group consisting of:

wherein
Q 1 is —C—R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl;
Q 2 is O, S or NH;
Hal is a nuclide or radionuclide of the halogen group selected from the group consisting of isotopes and radioisotopes of fluorine, iodine, bromine or astatine;
and wherein formula (I) comprises at least one isotope or radioisotope selected from fluorine, iodine, bromine or astatine;
and pharmaceutically acceptable salts thereof.

2 . A PSMA targeting ligand according to claim 1 , having the general formula (Ia):

wherein:
A is independently carboxylic acid, sulphonic acid, phosphonic acid, tetrazole or isoxazole;
n is an integer selected from the group consisting of 1, 2, 3 and 4;
m is an integer selected from the group consisting of 0 and 1;
o is an integer selected from the group consisting of 0 and 1;
is is selected from the group consisting of:

wherein
Q 1 is —C—R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl;
Q 2 is O, S or NH;
Hal is a nuclide or radionuclide of the halogen group selected from the group consisting of isotopes and radioisotopes of fluorine, iodine, bromine or astatine;
M is a chelating agent, that can comprise a metal;
R 1 is —CH—CH 2 —Z or —CH—CH 2 —Y;
wherein Z is selected from the group consisting of:

and Y is selected from the group consisting of:

wherein
Q 1 is —C—R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl;
Q 2 is O, S or NH;
Hal is a nuclide or radionuclide of the halogen group selected from the group consisting of isotopes and radioisotopes of fluorine, iodine, bromine or astatine;
R 2 is —CH—CH 2 —Y or —CH 2 —X—;
wherein X is an aromatic monocyclic or polycyclic ring system having 6 to 14 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;
and Y is selected from the group consisting of:

wherein
Q 1 is —C—R 3 or N, wherein R 3 is H or C 1 -C 5 alkyl;
Q 2 is O, S or NH;
Hal is a nuclide or radionuclide of the halogen group selected from the group consisting of isotopes and radioisotopes of fluorine, iodine, bromine or astatine;
and wherein formula (I) comprises at least one isotope or radioisotope selected from fluorine, iodine, bromine or astatine;
and pharmaceutically acceptable salts thereof.

3 . The PSMA targeting ligand according to claim 1 ,
wherein M is 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 (HBED-CC), 14,7-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), 4,7-triazacyclononane phosphinic acid (TRAP), 14,7-triazacyclononane methyl(2-carboxyethyl)phosphinic acid-4,7-bis(methyl(2-hydroxymethyl)phosphinic acid (NOPO), 3,6,9,15-tetraazabicyclo9.3.1.pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (PCTA), N′-(5-acetyl (hydroxy)aminopentyl-N-(5-(4-(5-aminopentyl)(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 (1B3M), 2-(p-isothiocyanatobenzyl)-4-methyl-DTPA (1M3B), and 1-(2)-methyl-4-isocyanatobenzyl-DTPA (MX-DTPA); and pharmaceutically acceptable salts thereof.

4 . The PSMA targeting ligand according to claim 3 , wherein M comprises a metal selected from the group consisting of Y, Lu, Tc, Zr, In, Sm, Re, Cu, Pb, Ac, Bi, Al, Ga, Ho and Sc.

5 . The PSMA targeting ligand according to claim 1 , wherein R 1 is —CH—CH 2 —Y and Hal is selected from the group consisting of 18 F, 19 F, 125 I, 123 I, 131 I, 124 I, 127 I, 211 At, 77 Br, 80 Br, 79 Br, and 81 Br

6 . The PSMA targeting ligand according to claim 1 , selected from the group consisting of:

wherein in compound Ii, Ij, Ik, Il, Im and In “I” is an isotope or radioisotope o

Assignees

• Rigshospitalet
• Univ Copenhagen
• Univ Denmark Tech Dtu
• Deutsches Krebsforschungszentrum Stiftung Desoeffentlichen Rechts
• Univ Freiburg Albert Ludwigs

Inventors

• Kjaer Andreas
• Herth Matthias Manfred
• Jensen Andreas Ingemann
• Eder Matthias
• Eder Ann-Christin

Classifications

• A61K2123/00

  Preparations for testing in vivo · CPC title

• A61K51/0406

  Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines · CPC title

• A61K51/044 Primary

  having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins (rifampin A61K51/0459) · CPC title

• A61K51/0402

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

• A61K51/0497 Primary

  conjugates with a carrier being an organic compounds · CPC title