Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-10907197-B2
Application number	US-201515507217-A
Country	US
Kind code	B2
Filing date	Aug 28, 2015
Priority date	Aug 29, 2014
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

Provided are imaging agents comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and methods of their use.

First claim

What is claimed is:

1. An imaging agent comprising a compound:
4-[5-(methoxymethoxy)-1-benzofuran-2-yl]-1-methyl-1H-pyrazole-3-carbonitrile;
2-[(dimethylamino)methyl]-6-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
2-bromo-6-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
5-bromo-2-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
4-iodo-6-(5-methoxy- 1-benzofuran-2-yl)pyrimidine-5-carbonitrile;
3-(5-hydroxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile;
4-(6-methoxynaphthalen-2-yl)pyridine-3-carbonitrile;
4-(6-methoxy-1H-1,3-benzodiazol-2-yl)pyridine-3-carbonitrile;
6-methoxy-2-[3-(1H-pyrazol-5-yl)pyridin-4-yl]-1,3-benzothiazole;
4-(6-methoxyquinolin-2-yl)pyridine-3-carbonitrile;
4-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
4-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
6-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
4-(1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
2-(6-methoxy-1,3-benzothiazol-2-yl)benzonitrile;
2-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile;
4-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-2-carbonitrile;
2-(6-methoxy-1,3-benzoxazol-2-yl)benzonitrile;
4-[6-(2-fluoroethoxy)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile;
4-(5-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
4-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile;
4-[5-(2-fluoroethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
3-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-4-carbonitrile;
5-bromo-3 -{5-bromofuro[2,3-b]pyridin-2-yl}-1,2-dihydropyridin-2-one;
2-{5-methoxyfuro[2,3-c]pyridin-2-yl}benzonitrile;
2-{5-bromofuro[2,3-b]pyridin-2-yl}benzonitrile;
2-{5-methoxyfuro[2,3-b]pyridin-2-yl}benzonitrile;
4-[5-(methoxymethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
4-(5-hydroxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
4-[5-(2-methoxyethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
2-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
4-{ 5-methoxyfuro [2,3-]pyridin-2-yl}pyridine-3-carbonitrile;
4-{6-methoxyfuro[3,2-b]pyridin-2-yl}pyridine-3-carbonitrile;
5-methoxy-2-(pyridin-4-yl)-1-benzofuran-3-carbonitrile;
4-[5-(2-hydroxyethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
2-{4,6,10-trioxa-12-azatricyclo[7.3.0.0 3 , 7 ]dodeca-1(9),2,7,11-tetraen-11-yl }benzonitrile;
4-{5-[(2-hydroxyethyl)(methyl)amino]-1-benzofuran-2-yl}pyridine-3-carbonitrile;
2-{2-methoxyfuro[2,3-d]pyrimidin-6-yl}benzonitrile;
4-(6-methoxy-1,3-benzoxazol-2-yl)pyridine-3-carbonitrile;
3-(5-methoxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile;
3-ethynyl-4-(5-methoxy-1-benzofuran-2-yl)pyridine;
4-(5-methoxy-3-methyl-1-benzofuran-2-yl)pyridine-3-carbonitrile; or
4-[(dimethylamino)methyl]-2-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
or a pharmaceutically acceptable salt thereof, wherein the compound is labeled with one or more positron-emitting radionuclides.

2. The imaging agent of claim 1 , wherein said one or more positron-emitting radionuclides are selected from: 11 C , 13 N , 15 O, 18 F, 76 Br, and 124 I.

3. A method of generating diagnostic images in an individual comprising administering an effective amount of an imaging agent of claim 1 to an individual, and generating an image of at least a part of said individual.

4. The method of claim 3 , wherein generating an image of at least a part of said individual comprises generating an image to detect the presence or absence of huntingtin protein (HTT protein) aggregates in the brain of said individual; and detecting the presence or absence of a pathologic process.

5. The method of claim 4 , wherein said HTT protein aggregates are present in the basal ganglia of said brain of said individual.

6. The method of claim 4 , wherein the pathologic process is a neurodegenerative disease.

7. The method of claim 6 , wherein the neurodegenerative disease is chosen from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Prion disease and spinocerebellar ataxias.

8. The method of claim 7 , wherein the neurodegenerative disease is Huntington's disease (HD).

9. The method of claim 3 , wherein said effective amount of said imaging agent comprises from about 0.1 to about 20 mCi.

10. The method of claim 3 , wherein said generating an image comprises positron emission tomography (PET) imaging, PET with concurrent computed tomography imaging (PET/CT), PET with concurrent magnetic resonance imaging (PET/MRI), or a combination thereof.

11. The method of claim 10 , wherein said generating an image comprises PET imaging.

12. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
4-[5-(methoxymethoxy)-1-benzofuran-2-yl]-1-methyl-1H-pyrazole-3-carbonitrile;
2-[(dimethylamino)methyl]-6-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
2-bromo-6-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
5-bromo-2-(5-methoxy-1-benzofuran-2-yl)benzonitrile;
4-iodo-6-(5-methoxy-1-benzofuran-2-yl)pyrimidine-5-carbonitrile;
3-(5-hydroxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile;
4-(6-methoxynaphthalen-2-yl)pyridine-3-carbonitrile;
4-(6-methoxy-1H-1,3-benzodiazol-2-yl)pyridine-3-carbonitrile;
6-methoxy-2-[3-(1H-pyrazol-5-yl)pyridin-4-yl]-1,3-benzothiazole;
4-(6-methoxyquinolin-2-yl)pyridine-3-carbonitrile;
4-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
4-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
6-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
4-(1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
2-(6-methoxy-1,3-benzothiazol-2-yl)benzonitrile;
2-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
4-[6-(dimethylamino)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile;
4-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-2-carbonitrile;
2-(6-methoxy-1,3-benzoxazol-2-yl)benzonitrile;
4-[6-(2-fluoroethoxy)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile;
4-(5-methoxy-1,3-benzothiazol-2-yl)pyridine-3-carbonitrile;
4-[6-(trifluoromethyl)-1,3-benzothiazol-2-yl]pyridine-3-carbonitrile;
4-[5-(2-fluoroethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
3-(6-methoxy-1,3-benzothiazol-2-yl)pyridine-4-carbonitrile;
5-bromo-3-{5-bromofuro[2,3-b]pyridin-2-yl}-1,2-dihydropyridin-2-one;
2-{5-methoxyfuro[2,3-c]pyridin-2-yl}benzonitrile;
2-{5-bromofuro[2,3-b]pyridin-2-yl}benzonitrile;
2-{5-methoxyfuro[2,3-b]pyridin-2-yl}benzonitrile;
4-[5-(methoxymethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
4-(5-hydroxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
4-[5-(2-methoxyethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
2-(5-methoxy-1-benzofuran-2-yl)pyridine-3-carbonitrile;
4-{5-methoxyfuro[2,3-c]pyridin-2-yl}pyridine-3-carbonitrile;
4-{6-methoxyfuro[3,2-b]pyridin-2-yl}pyridine-3-carbonitrile;
5-methoxy-2-(pyridin-4-yl)-1-benzofuran-3-carbonitrile;
4-[5-(2-hydroxyethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;
2-{4,6,10-trioxa-12-azatricyclo[7.3.0.0 3 , 7 ]dodeca-1(9),2,7,11-tetraen-11-yl}benzonitrile;
4-{5-[(2-hydroxyethyl)(methyl)amino]-1-benzofuran-2-yl}pyridine-3-carbonitrile;
2-{2-methoxyfuro[2,3-d]pyrimidin-6-yl}benzonitrile;
4-(6-methoxy-1,3-benzoxazol-2-yl)pyridine-3-carbonitrile;
3-(5-methoxy-1-benzofuran-2-yl)-5H,6H-imidazo[2,1-b][1,3]thiazole-2-carbonitrile;
3-ethynyl-4-(5-methoxy-1-benzofuran-2-yl)pyridine;
4-(5-methoxy-3-methyl-1-benzofuran-2-yl)pyridine-3-carbonitrile; or
4-[(dimethylamino)methyl]-2-(5-methoxy-1-benzofuran-2-yl)benzonitrile.

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Wityak John
• Bard Jonathan
• Brown Christopher John
• Prime Michael Edward
• Weddell Derek Alexander
• Walter Daryl Simon
• Giles Paul Richard
• Wigginton Ian James
• Taylor Malcolm George
• Galan Sébastien René Gabriel
• Johnson Peter David
• Krülle Thomas Martin
• Morao Inaki
• Clark-Frew Daniel

Classifications

• A61K51/0455 Primary

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K51/0453

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• A61K51/0419 Primary

  having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide · CPC title

• C07D473/00

  Heterocyclic compounds containing purine ring systems · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title