Probes for imaging huntingtin protein

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.