Probes for imaging huntingtin protein

Patent metadata

Field	Value
Publication number	US-11071793-B2
Application number	US-201515507214-A
Country	US
Kind code	B2
Filing date	Aug 28, 2015
Priority date	Aug 29, 2014
Publication date	Jul 27, 2021
Grant date	Jul 27, 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 of Formula

or a pharmaceutically acceptable salt thereof, wherein
Z 1 , Z 2 , Z 3 , and Z 4 are independently chosen from C, CH, and N, provided that one of Z 1 , Z 2 , Z 3 , and Z 4 is C and at least one of Z 1 , Z 2 , Z 3 , and Z 4 is CH;
R 1 is 2,3-dihydropyridazin-3-one-6-yl optionally substituted with lower alkyl;
L 1 is O;
L 2 is (CH 2 ) m where m is 1 or 2;
R 2 is heteroaryl or heteroaryl substituted with hydroxyl or lower alkoxy;
R 5 is oxo; and
n is 0 or 1;
wherein the compound, or a pharmaceutically acceptable salt thereof, is labeled with one or more positron-emitting radionuclides.

2. The imaging agent of claim 1 , wherein m is 1.

3. The imaging agent of claim 1 , wherein R 2 is heteroaryl substituted with hydroxyl or lower alkoxy.

4. The imaging agent of claim 1 , wherein R 2 is pyridin-2-yl, pyrimidin-5-yl, pyrazin-2-yl, and pyrimidin-5-yl, each of which is optionally substituted with hydroxyl or lower alkoxy.

5. The imaging agent of claim 1 , wherein three of Z 1 , Z 2 , Z 3 , and Z 4 are CH and one is C.

6. The imaging agent of claim 1 , wherein Z 1 is N, two of Z 2 , Z 3 , and Z 4 are CH and one is C.

7. The imaging agent of claim 1 , wherein Z 2 is N and Z 1 , Z 3 , and Z 4 are CH or C.

8. The imaging agent of claim 1 , wherein Z 2 and Z 4 are one of Z 1 and Z 3 is CH and the other is C.

9. An imaging agent comprising a compound chosen from:
2-(5-methoxy-2,3-dihydro-1H-isoindol-2-yl)pyridine-3-carbonitrile;
2-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile;
2-[5-(pyrimidin-5-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]pyridine-3-carbonitrile;
4-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile;
4-(5-methoxy-2,3-dihydro-1H-isoindol-2-yl)pyrimidine-5-carbonitrile;
4-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyrimidine-5-carbonitrile;
4-{5-[(5-hydroxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyridine-3-carbonitrile;
4-(5-methoxy-2,3-dihydro-1H-isoindol-2-yl)pyridine-3-carbonitrile;
4-[5-(pyrimidin-5-ylmethoxy)-2,3-dihydro-1H-isoindol-2-yl]pyridine-3-carbonitrile;
5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-4-yl)-2,3-dihydro-1H-isoindole;
4-[5-(benzyloxy)-2,3-dihydro-1H-isoindol-2-yl]pyrimidine-5-carbonitrile;
4-{5-[(5-hydroxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}pyrimidine-5-carbonitrile;
6-{5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-1H-isoindol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; and
5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-4-yl)-2,3-dihydro-1H-isoindol-1-one;

or a pharmaceutically acceptable salt thereof, and wherein the compound is labeled with one or more positron-emitting radionuclides.

10. The imaging agent of claim 1 , wherein said compound contains one or more positron-emitting radionuclides selected from: 11 C, 13 N, 15 O, and 18 F.

11. 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.

12. The method of claim 11 , 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.

13. The method of claim 12 , wherein said HTT protein aggregates are present in the basal ganglia of said brain of said individual.

14. The method of claim 12 , wherein the pathologic process is a neurodegenerative disease.

15. The method of claim 14 , wherein the neurodegenerative disease is chosen from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Prion disease and spinocerebellar ataxias.

16. The method of claim 15 , wherein the neurodegenerative disease is Huntington's disease (HD).

17. The method of claim 11 , wherein said effective amount of said imaging agent comprises from about 0.1 to about 20 mCi.

18. The method of claim 17 , wherein said effective amount of said imaging agent comprises about 10 mCi.

19. The method of claim 11 , 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.

20. The method of claim 19 , wherein said generating an image comprises PET imaging.

Assignees

• Chdi Foundation Inc

Inventors

• Dominguez Celia
• Wityak John
• Bard Jonathan
• Brown Christopher John
• Krülle Thomas Martin
• Clark-Frew Daniel
• Hayes Sarah

Classifications

• A61K51/0459 Primary

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• A61K51/0455 Primary

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

• A61K51/0446

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07D403/04 Primary

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

• C07D401/14

  containing three or more hetero rings · CPC title