HSP90-targeted cardiac imaging and therapy

Patent metadata

Field	Value
Publication number	US-10201623-B2
Application number	US-201414776143-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Feb 12, 2019
Grant date	Feb 12, 2019

Abstract

The present invention provides new methods for cardiac imaging and related medical applications thereof. In some embodiments, the present invention provides a method for the diagnosis of cardiovascular diseases, conditions, or disorders. In some embodiments, the present invention provides a method for the treatment or prevention of cardiovascular diseases, conditions, or disorders. In some embodiments, the present invention provides methods for monitoring the effect of cancer treatment on the heart, and/or methods for monitoring a cancer treatment regimen. In some embodiments, the present invention provides a method for selecting subjects for a test or treatment. In some embodiments, the present invention provides a method for determining the dosage of a drug. In some embodiments, the present invention provides methods for determining the risk of a cardiovascular disease, for assessing risk of a cardiovascular disease, and/or for determining the risk of heart attack.

First claim

What is claimed is:

1. A method for imaging cardiac tissue in a subject in need thereof, comprising steps of:
(a) administering to the subject a labeled compound that preferentially binds to stress specific Hsp90 as compared to other forms of Hsp90; and
(b) imaging the cardiac tissue of the subject by detecting the labeled compound in the subject;
wherein a cardiac stress test is performed on the subject and wherein the labeled compound is a labeled compound of formula I:

or its pharmaceutically acceptable salt thereof, wherein:
Y is CH, N or O;
R is hydrogen, a CH 1 to C 10 alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally comprising one or more heteroatoms, or a targeting moiety connected to N9 via a linker;
X 4 is hydrogen or halogen;
X 3 is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2 is alkyl;
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 alkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C═SR 2 , NSO 2 X 5 , C═OR 2 , where X 5 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl; and

X 1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X 1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, NH 2 OH, CN, SO 2 X 5 , NO 2 , NO, C═SR 2 , NSO 2 X 5 , C═OR 2 , where X 5 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl, or O-alkyl, C 1 to C 6 alkyl or alkoxy, or wherein X 1 has the formula —O—(CH 2 ) n —O—, wherein n is an integer from 0 to 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring;
wherein each hydrogen of the compound of formula I is optionally and independently substituted with a group that can be detected by a medical imaging technique, and/or at least one atom in the compound is optionally enriched in an isotope that can be detected by a medical imaging technique.

2. The method of claim 1 , further comprising comparing the data of a first cardiac position of an image obtained in step (b) to those of a second cardiac position, wherein the second cardiac position is from another cardiac image or a different position of the same cardiac image.

3. The method of claim 2 , wherein the comparison or analysis of images comprises identifying abnormal signal compared to a reference, wherein the abnormal signal indicates an increased risk of a cardiovascular condition, disorder, or disease.

4. The method of claim 3 , wherein the abnormal signal indicates increased risk of coronary artery disease, myocardial dysfunction, and/or abnormal myocardial blood flow.

5. The method of claim 3 , wherein the cardiovascular disease, disorder, or condition is associated with stress-specific Hsp90.

6. The method of claim 2 , further comprising performing a nuclear stress test on the subject.

7. The method of claim 1 , further comprising performing a nuclear stress test on the subject.

8. The method of claim 1 , wherein at least one atom in the compound is optionally enriched in an isotope that can be detected by a medical imaging technique.

9. The method of claim 1 , wherein the labeled compound inhibits Hsp90.

10. The method of claim 1 , wherein the labeled compound is administered before, during, or after administration of a non-radioactive therapeutic compound.

11. The method of claim 10 , wherein the non-radioactive therapeutic compound has the structure of formula X:

or its pharmaceutically acceptable salt thereof, wherein:
Y is CH, N or O;
R is hydrogen, a C 1 to C 10 alkyl, alkenyl, alkynyl, or an alkoxyalkyl group, optionally comprising one or more heteroatoms, or a targeting moiety connected to N9 via a linker;
X 4 is hydrogen or halogen;
X 3 is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2 is alkyl;
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 alkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C═SR 2 , NSO 2 X 5 , C═OR 2 , where X 5 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl; and
X 1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X 1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, NH 2 OH, CN, SO 2 X 5 , NO 2 , NO, C═SR 2 , NSO 2 X 5 , C═OR 2 , where X 5 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl, or O-alkyl, C 1 to C 6 alkyl or alkoxy, or wherein X 1 has the formula —O—(CH 2 ) n —O—, wherein n is an integer from 0 to 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring;

or the non-radioactive therapeutic compound has a structure depicted in any of groups (i) to (vi):

or a pharmaceutically acceptable salt thereof, wherein:
(a) each of Z 1 Z 2 and Z 3 is independently CH or N;
(b) Y is CH 2 , O, or S;
(c) Xa, Xb, Xc and Xd are independently selected from CH, CH 2 , O, N, NH, S, carbonyl, fluoromethylene, and difluoromethylene selected so as to satisfy valence, wherein each bond to an X group is either a single bond or a double bond;
(d) X 2 is I
(e) X 4 is hydrogen or halogen; and
(f) R is straight-chain- or branched- substituted or unsubstituted alkyl, straight-chain- or branched- substituted or unsubstituted alkenyl, straight-chain- or branched- substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl, wherein the R group is optionally interrupted by
—S(O)N(R A )—, —NR A S(O)—, —SO 2 N(R A )—, —NR A SO 2 —, —C(O)N(R A )—, or —NR A C(O)—, and/or the R group is optionally terminated —S(O)NR A R B , —NR A S(O)R B ,—SO 2 NR A R B , —NR A SO 2 R B , —C(O)NR A R B , or —NR A C(O)R B , wherein each R A and R B is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, and alkylheteroarylalkyl;

or a pharmaceutically acceptable salt thereof, wherein:
Y is CH 2 or S;
X 4 is H or halogen
X 2 is I; and

R is —(CH 2 ) m —N—R 10 R 11 R 12 or —(CH 2 ) m —N—R 10 R 11 , where m is 2 or 3 and where R 10 -R 12 are independently selected from hydrogen, methyl, ethyl, ethenyl, ethynyl, propyl, hydroxyalkyl, isopropyl, t-butyl, isobutyl, cyclopentyl, a 3-membered ring including the nitrogen or a 6-membered ring including the N and optionally an additional heteroatom with substitue

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Dunphy Mark
• Strauss H William
• Chiosis Gabriela

Classifications

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• G01N2800/325

  Heart failure or cardiac arrest, e.g. cardiomyopathy, congestive heart failure · CPC title

• G01N2333/47

  Assays involving proteins of known structure or function as defined in the subgroups · CPC title

• G01N33/6893

  related to diseases not provided for elsewhere · CPC title

• G01N33/60

  involving radioactive labelled substances · CPC title