Long-lived gadolinium based tumor targeted imaging and therapy agents

Patent metadata

Field	Value
Publication number	US-10265398-B2
Application number	US-201615343580-A
Country	US
Kind code	B2
Filing date	Nov 4, 2016
Priority date	Nov 6, 2015
Publication date	Apr 23, 2019
Grant date	Apr 23, 2019

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 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 aroalkyl; and
b is 1 or 2
wherein the chelating agent is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A); 1,4,7-triazacyclononane-1,4-diacetic acid (NODA); 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA); 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 1,4,7-triazacyclononane, 1-glutaric acid-4,7,10-diacetic acid (NODAGA); 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A); diethylene triamine pentaacetic acid (DTPA), its diester; 2-cyclohexyl diethylene triamine pentaacetic acid (CHX-A″-DTPA); deforoxamine (DFO); 1,2-[[6-carboxypyridin-2-yl]methylamino]ethane (H 2 dedpa); and DADA, wherein DADA has the structure:

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

3. The compound of claim 1 , wherein the chelating agent chelated to the gadolinium atom is selected from the group consisting of:

4. The compound of claim 1 , wherein the compound is selected from the group consisting of:

wherein the selected compound is chelated to a gadolinium atom.

5. The compound of claim 4 , wherein the compound is:

6. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

7. A method for detecting or imaging one or more cancer tumor cells in a biological sample, comprising:
(a) contacting the biological sample with a compound of claim 1 ; 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.

8. The method of claim 7 , wherein the step of identifying individual cells or regions within the biological sample that are emitting signals characteristic of gadolinium is performed by magnetic resonance imaging (MRI).

9. The method of claim 7 , wherein the biological sample is part or all of a subject.

10. The method of claim 7 , wherein the biological sample is obtained from a subject.

11. The method of claim 9 , wherein the subject is a human.

12. The method of claim 7 , wherein the cancer cells are adult solid tumor cells or pediatric solid tumor cells.

13. The method of claim 12 , wherein the cancer cells are selected from the group consisting of melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell cancer cells, intestinal cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewings sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, Wilms' tumor cells, and pediatric brain tumor cells.

14. A method of diagnosing cancer in a subject, comprising performing the method of claim 7 , wherein the biological sample is obtained from, part of, or all of a subject, and whereby if cancer cells are detected or imaged, the subject is diagnosed with cancer.

15. A method of monitoring the efficacy of a cancer therapy in a human subject, comprising performing the method of claim 7 at two or more different times on the biological sample, wherein the biological sample is obtained from, part of, or all of a subject, and whereby the change in strength of the signals characteristic of the gadolinium between the two or more different times is correlated with the efficacy of the cancer therapy.

16. A method of treating a cancer in a subject by neutron capture therapy, comprising:
(a) administering to a subject having cancer a composition comprising a compound of claim 1 ; and
(b) radiating the subject with epithermal neutrons;
whereby the compound absorbs the neutrons and subsequently emits high-energy charged particles, thereby treating the cancer.

17. The method of claim 16 , wherein the cancer that is treated is an adult solid tumor or a pediatric solid tumor.

18. The method of claim 17 , wherein the cancer is selected from the group consisting of melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell cancer, intestinal cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, Ewings sarcoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, Wilms' tumor, and pediatric brain tumors.

Assignees

• Wisconsin Alumni Res Found

Inventors

• Weichert Jamey
• Pinchuk Anatoly
• Tomé Wolfgang Axel

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• G01N2458/15

  Non-radioactive isotope labels, e.g. for detection by mass spectrometry · CPC title

• G01N33/60

  involving radioactive labelled substances · CPC title

• G01N33/58

  involving labelled substances (G01N33/53 takes precedence) · CPC title

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title