Prodrugs of 2-PMPA for healthy tissue protection during PSMA-targeted cancer imaging or radiotherapy

Patent metadata

Field	Value
Publication number	US-12508271-B2
Application number	US-201816604663-A
Country	US
Kind code	B2
Filing date	Apr 11, 2018
Priority date	Apr 11, 2017
Publication date	Dec 30, 2025
Grant date	Dec 30, 2025

Abstract

The use of a class of prodrugs of 2-PMPA that alter tissue distribution of 2-PMPA to non-prostate tissues is disclosed. The presently disclosed prodrugs preferentially distribute to healthy tissues including the kidney, lacrimal glands, and salivary glands, which represent sites of off-target binding and toxicity for PSMA-targeted prostate cancer imaging agents and therapies. Accordingly, the 2-PMPA prodrugs can be used to pretreat, bind to, and shield the kidney and salivary glands from PSMA-targeted cytotoxic or radiotherapy.

First claim

That which is claimed:

1 . A method for preventing or reducing uptake of a prostate-specific membrane antigen (PSMA)-targeted imaging or therapeutic agent in an organ selected from a kidney, a salivary gland, and a lacrimal gland, while sparing tumor uptake, the method comprising administering to a subject being treated with a PSMA-targeted agent a prodrug of 2-(phosphonomethyl) pentanedioic acid (2-PMPA) in an amount effective to prevent or reduce uptake of the PSMA-targeted agent in the organ selected from a kidney, a salivary gland, and a lacrimal glan, wherein the prodrug of 2-PMPA is:

and
pharmaceutically acceptable salts thereof;
wherein the prodrug of 2-PMPA is administered to the subject before the PSMA-targeted imaging or therapeutic agent is administered; or
wherein the prodrug of 2-PMPA is administered to the subject simultaneously with the PSMA-targeted imaging or therapeutic agent;
wherein the PSMA-targeted imaging or therapeutic agent has a PSMA-binding moiety selected from a glycine-ureido-lysine motif having the following chemical structure:

wherein R is H or brominated benzyl; or
a phosphoramidate motif having the following chemical structure:

2 . The method of claim 1 , wherein the PSMA-targeted imaging or therapeutic agent is selected from the group consisting of 177Lu-PSMA-617, 131I-MIP-1095, 177Lu-PSMA-I&T, 177Lu-PSMA-R2, 225Ac-PSMA-617, CTT1403, CTT1700, 68Ga-PSMA-11, 18F-DCFPyL, CTT1057, 68Ga-PSMA-R2, and 68Ga-PSMA-617.

3 . The method of claim 2 , wherein the PSMA-targeted therapeutic agent is a radiotherapeutic administered in a cumulative amount from about 3 GBq to about 100 GBq.

4 . The method of claim 3 , wherein the PSMA-targeted radiotherapeutic is administered in a cumulative amount from about 52 GBq to about 100 GBq.

5 . The method of claim 2 , wherein the PSMA-targeted therapeutic agent and 2-PMPA prodrug are administered for about 1 to about 15 treatment cycles.

6 . The method of claim 5 , wherein the PSMA-targeted therapeutic and 2-PMPA prodrug are administered for about 6 to about 15 treatment cycles.

7 . The method of claim 1 , wherein the prodrug of 2-PMPA is administered to the subject before the PSMA-targeted imaging or therapeutic agent is administered.

8 . The method of claim 1 , wherein the prodrug of 2-PMPA is administered to the subject simultaneously with the PSMA-targeted imaging or therapeutic agent.

9 . The method of claim 1 , wherein the organ is a kidney.

10 . The method of claim 1 , wherein the organ is a lacrimal gland.

11 . The method of claim 1 , wherein the organ is a salivary gland.

12 . The method of claim 1 , wherein the PSMA-targeted imaging or therapeutic agent has a PSMA-binding moiety having a glycine-ureido-lysine motif having the following chemical structure:

wherein R is H or brominated benzyl.

13 . The method of claim 12 , wherein the PSMA-targeted imaging or therapeutic agent is selected from 177 Lu-PSMA-617, 131 I-MIP-1095, 177 Lu-PSMA-I&T, 177 Lu-PSMA-R2, 225 Ac-PSMA-617, 68 Ga-PSMA-11, 18 F-DCFPyL, 68 Ga-PSMA-R2, and 68 Ga-PSMA-617.

14 . The method of claim 1 , wherein the PSMA-targeted imaging or therapeutic agent has a PSMA-binding moiety having a phosphoramidate motif having the following chemical structure:

15 . The method of claim 14 , wherein the PSMA-targeted imaging or therapeutic agent is selected from CTT1403, CTT1700, and CTT1057.

Assignees

• Univ Johns Hopkins
• Adarga Llc

Inventors

• Slusher Barbara
• Nedelcovych Michael
• Rais Rana
• Kratochwil Clemens

Classifications

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• A61K51/0402

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

• A61K31/664

  Amides of phosphorus acids · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title

• A61K31/663

  Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid · CPC title