Long-lived gadolinium based tumor targeted imaging and therapy agents

Patent metadata

Field	Value
Publication number	US-12564635-B2
Application number	US-202318175246-A
Country	US
Kind code	B2
Filing date	Feb 27, 2023
Priority date	Nov 6, 2015
Publication date	Mar 3, 2026
Grant date	Mar 3, 2026

Abstract

Alkylphosphocholine analogs incorporating a chelating moiety that is chelated to gadolinium are disclosed herein. The alkylphophocholine analogs are compounds having the formula:

or a salt thereof. R 1 includes a chelating agent that is chelated to a gadolinium atom; a is 0 or 1; n is an integer from 12 to 30; m is 0 or 1; Y is —H, —OH, —COOH, —COOX, —OCOX, or —OX, wherein X is an alkyl or an arylalkyl; R 2 is —N + H 3 , —N + H 2 Z, —N + HZ 2 , or —N + Z 3 , wherein each Z is independently an alkyl or an aroalkyl; and b is 1 or 2. The compounds can be used to detect solid tumors or to treat solid tumors. In detection/imaging applications, the gadolinium emits signals that are detectable using magnetic resonance imaging. In therapeutic treatment, the gadolinium emits tumor-targeting charged particles when exposed to epithermal neutrons.

First claim

The invention claimed is:

1 . A pharmaceutical composition, comprising:
(a) an effective amount of a compound having the formula:

or a salt thereof, wherein:
R 1 comprises a chelating agent that is chelated to one or more gadolinium (Gd) atoms;
a is 0 or 1;
n is an integer from 12 to 30;
m is 0 or 1;
Y is selected from the group consisting of —H, —OH, —COOH, —COOX, —OCOX, and —OX, wherein X is an alkyl or an arylalkyl;
R 2 is selected from the group consisting of —N + H 3 , —N + H 2 Z, —N + HZ 2 , and —N + Z 3 , wherein each Z is independently an alkyl or an arylalkyl; and
b is 1 or 2; and
(b) a pharmaceutically acceptable carrier.

2 . The pharmaceutical composition of claim 1 , wherein the one or more gadolinium atoms are in the form of a Gd(III) ion.

3 . The pharmaceutical composition of claim 1 , wherein a is 1.

4 . The pharmaceutical composition of claim 1 , wherein a is 0.

5 . The pharmaceutical composition of claim 1 , wherein m is 1.

6 . The pharmaceutical composition of claim 5 , wherein n is an integer between 12 and 20.

7 . The pharmaceutical composition of claim 5 , wherein Y is —OCOX, —COOX, or —OX.

8 . The pharmaceutical composition of claim 7 , wherein X is —CH 2 CH 3 or —CH 3 .

9 . The pharmaceutical composition of claim 1 , wherein m is 0.

10 . The pharmaceutical composition of claim 1 , wherein b is 1.

11 . The pharmaceutical composition of claim 1 , wherein n is 18.

12 . The pharmaceutical composition of claim 1 , wherein R 2 is —N + Z 3 .

13 . The pharmaceutical composition of claim 12 , wherein each Z is independently —CH 2 CH 3 or —CH 3 .

14 . The pharmaceutical composition of claim 13 , wherein each Z is —CH 3 .

15 . The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for topical, enteral, and/or parenteral administration.

16 . A method for detecting or imaging one or more cancer tumor cells in a biological sample, comprising:
(a) administering to a biological sample an effective amount of a compound having the formula:

or a salt thereof, wherein:
R 1 comprises a chelating agent that is chelated to one or more gadolinium (Gd) atoms;
a is 0 or 1;
n is an integer from 12 to 30;
m is 0 or 1;
Y is selected from the group consisting of —H, —OH, —COOH, —COOX, —OCOX, and —OX, wherein X is an alkyl or an arylalkyl;
R 2 is selected from the group consisting of —N + H 3 , —N + H 2 Z, —N + HZ 2 , and —N + Z 3 , wherein each Z is independently an alkyl or an arylalkyl; and
b is 1 or 2; and
(b) identifying individual cells or regions within the biological sample that are emitting signals characteristic of gadolinium, whereby one or more cancer tumor cells are detected or imaged.

17 . The method of claim 16 , wherein step (b) is performed by magnetic resonance imaging (MRI).

18 . The method of claim 16 , wherein the biological sample is part or all of a subject.

19 . A method of diagnosing cancer in a subject, comprising: performing the method of claim 16 , wherein the biological sample is obtained from, part of, or all of a subject, and whereby if cancer cell are detected or imaged, the subject is diagnosed with cancer.

20 . A method of treating cancer in a subject, comprising:
(a) administering an effective amount of a compound to a subject having cancer, the compound having the formula:

or a salt thereof, wherein:
R 1 comprises a chelating agent that is chelated to one or more gadolinium (Gd) atoms;
a is 0 or 1;
n is an integer from 12 to 30;
m is 0 or 1;
Y is selected from the group consisting of —H, —OH, —COOH, —COOX, —OCOX, and —OX, wherein X is an alkyl or an arylalkyl;
R 2 is selected from the group consisting of —N + H 3 , —N + H 2 Z, —N + HZ 2 , and —N + Z 3 , wherein each Z is independently an alkyl or an arylalkyl; and
b is 1 or 2;
(b) identifying individual cells or regions within the subject that are emitting signals characteristic of gadolinium; and
(c) directing an external radiotherapy beam to the identified individual cells or regions within the subject.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Weichert Jamey
• Pinchuk Anatoly
• Tome Wolfgang Axel

Classifications

• G01N33/60

  involving radioactive labelled substances · CPC title

• C07F9/10

  Phosphatides, e.g. lecithin · CPC title

• A61N2005/109

  Neutrons · CPC title

• A61N5/1077

  Beam delivery systems · CPC title

• A61N5/1048

  Monitoring, verifying, controlling systems and methods · CPC title