Compound, composition, and method for detecting caspase activity and/or apoptosis

Patent metadata

Field	Value
Publication number	US-10294271-B1
Application number	US-201414183480-A
Country	US
Kind code	B1
Filing date	Feb 18, 2014
Priority date	Feb 15, 2013
Publication date	May 21, 2019
Grant date	May 21, 2019

Abstract

Molecular probe suitable for quantification of caspase activity in vivo using positron emission tomography (PET). Embodiments of the present invention can detect apoptosis in tumors and as a novel, potentially translatable biomarker for predicting response to personalized medicine.

First claim

We claim:

1. A method of imaging a molecular event in a sample, comprising:
(a) administering to said sample a probe having an affinity for a target, the probe comprising a compound of the following:

wherein:
R 1 is selected from
(i) alkyl-halogen, CO-alkyl-halogen, CO-phenyl, CO-alkyl-phenyl, CO-pyridinyl, wherein alkyl is optionally substituted with one or more R 7 , and phenyl or pyridinyl is optionally halogen-substituted;

X is iodine or fluorine;
R 3 is halogen;
R 5 is selected from alkyl, alkoxy;
R 7 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 5 R 5 , S(O) 0-2 NR 5 R 5 , CSNH 2 ;
X 1 is selected from alkyl, alkoxy, R 5 —C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 7 ; and
X 2 is H;
X 3 is independently C, CR 7 , N, NR 7 ;
and pharmaceutically acceptable salts thereof; and
(b) detecting a signal from said probe.

2. The method of claim 1 , wherein the molecular event is caspase activity.

3. The method of claim 1 , wherein the detecting step is with positron emission tomography (PET).

4. The method of claim 1 , wherein the compound is of the following formula:

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein said sample is at least one of cells, tissue, cellular tissue, serum, cell extract, bodily fluids and wherein the administration step is in vivo or in vitro.

6. The method of claim 1 , wherein said molecular event is at least one of cell proliferation, apoptosis, and caspase activity.

7. A compound of the following formula:

wherein:
R 1 is selected from
(i) alkyl-halogen, CO-alkyl-halogen, CO-phenyl, CO-alkyl-phenyl, CO-pyridinyl, wherein alkyl is optionally substituted with one or more R 7 , and phenyl or pyridinyl is optionally halogen-substituted;

X is iodine or fluorine;
R 3 is halogen;
R 5 is selected from alkyl, alkoxy;
R 7 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 5 R 5 , S(O) 0-2 NR 5 R 5 , CSNH 2 ;
X 1 is selected from alkyl, alkoxy, R 5 —C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 7 ; and
X 2 is H;
X 3 is independently C, CR 7 , N, NR 7 ;
and pharmaceutically acceptable salts thereof.

8. The compound of claim 7 , of the following formula:

and pharmaceutically acceptable salts thereof.

9. A method of quantifying the progression of a disease state in a subject, comprising:
(a) administering to a first sample of the subject a probe having an affinity for a target, the probe comprising a compound of the following:

wherein:
R 1 is selected from
(i) alkyl-halogen, CO-alkyl-halogen, CO-phenyl, CO-alkyl-phenyl, CO-pyridinyl, wherein alkyl is optionally substituted with one or more R 7 , and phenyl or pyridinyl is optionally halogen-substituted;

X is iodine or fluorine;
R 3 is halogen;
R 5 is selected from alkyl, alkoxy;
R 7 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 5 R 5 , S(O) 0-2 NR 5 R 5 , CSNH 2 ;
X 1 is selected from alkyl, alkoxy, R 5 -C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 7 ; and
X 2 is H;
X 3 is independently C, CR 7 , N, NR 7 ;
and pharmaceutically acceptable salts thereof;
(b) detecting a signal from said probe;
(c) after a period of time from step (b), administering to a second sample of the subject a probe having an affinity for a target, the probe comprising a compound of the following:

wherein:
R 1 is selected from
(i) alkyl-halogen, CO-alkyl-halogen, CO-phenyl, CO-alkyl-phenyl, CO-pyridinyl, wherein alkyl is optionally substituted with one or more R 7 , and phenyl or pyridinyl is optionally halogen-substituted;

X is iodine or fluorine;
R 3 is halogen;
R 5 is selected from alkyl, alkoxy;
R 7 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 5 R 5 , S(O) 0-2 NR 5 R 5 , CSNH 2 ;
X 1 is selected from alkyl, alkoxy, R 5 -C 3-8 membered ring containing C, O, S and/or N, optionally substituted with one or more R 7 ; and
X 2 is H;
X 3 is independently C, CR 7 , N, NR 7 ; and
pharmaceutically acceptable salts thereof;
(d) detecting a second signal; and
(e) comparing the first signal with the second signal to determine the progress of a disease state.

10. The method of claim 9 , wherein said sample is at least one of cells, tissue, cellular tissue, serum, cell extract, bodily fluid.

11. The method of claim 9 , wherein the probe is a compound of the following formula:

or a pharmaceutically acceptable salt thereof; and a pharmaceutical carrier.

12. A method of determining the presence of a disease state, comprising:
(a) administering to a first sample of the subject a probe having an affinity for a target, the probe comprising a compound of the following:

wherein:
R 1 is selected from
(i) alkyl-halogen, CO-alkyl-halogen, CO-phenyl, CO-alkyl-phenyl, CO-pyridinyl, wherein alkyl is optionally substituted with one or more R 7 , and phenyl or pyridinyl is optionally halogen-substituted;

X is iodine or fluorine;
R 3 is halogen;
R 5 is selected from alkyl, alkoxy;
R 7 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, aryl, benzyl, heteroaryl, halogen, CN, CF 3 , CONR 5 R 5 , S(O) 0-

Assignees

• Univ Vanderbilt

Inventors

• Manning H Charles
• Hight Matthew R

Classifications

• C07K5/08

  Tripeptides · CPC title

• G01N33/573 Primary

  for enzymes or isoenzymes · CPC title

• C07K5/10 Primary

  Tetrapeptides · CPC title

• C07K5/081 Primary

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• G01N2333/96413

  Cysteine endopeptidases (3.4.22) · CPC title