Compounds and probes for imaging huntingtin protein

1. A compound of Formula (I):

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof,

wherein:

Z 1 and Z 2 are each independently CH, or one of Z 1 and Z 2 is N and the other is CH;

Z 3 is N or CH;

L 1 is —O—C 1-4 alkylene;

one of X 1 and X 2 is N-L 2 -R 2 and the other is CH 2 ;

X 3 is CH 2 or —O—CH 2 —;

L 2 is —C(═O)—;

R 1 is heteroaryl optionally substituted with one or two substituents independently selected from hydroxy, alkyl, alkoxy, haloalkoxy, and —N(R 4 ) 2 ;

R 2 is aryl, heteroaryl, heterocycloalkyl, or heterocycloalkenyl, each of which is substituted with one or two substituents independently selected from halogen, haloalkyl, hydroxy, alkyl, alkoxy, haloalkoxy, heteroaryl, and —N(R 4 ) 2 ;

wherein when R 2 is substituted with alkyl, the alkyl is optionally substituted with alkenyl or alkoxy;

wherein when R 2 is substituted with alkoxy, the alkoxy is optionally substituted with alkenyl or alkoxy;

p is 0, 1, or 2;

each R 3 is independently C 1-4 alkyl; and

each R 4 is independently H or C 1-4 alkyl.

2. The compound of claim 1 , of Formula (Ha):

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

3. The compound of claim 1 , of Formula (IIb):

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

4. The compound of claim 1 , of Formula (Ma):

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

5. The compound of claim 1 , of Formula (Mb):

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

6. The compound of claim 1 , of Formula (Mc):

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

7. The compound of claim 1 , wherein R 1 is pyridinyl optionally substituted with one or two substituents independently selected from hydroxy, alkyl, alkoxy, and haloalkoxy.

8. The compound of claim 1 , wherein R 1 is pyridinyl optionally substituted with methoxy.

9. The compound of claim 1 , wherein R 1 is

10. The compound of claim 1 , wherein -L 1 -R 1 is

11. The compound of claim 1 , wherein Z 1 and Z 2 are each independently CH.

12. The compound of claim 1 , wherein one of Z 1 and Z 2 is N and the other is CH.

13. The compound of claim 12 , wherein Z 1 is N and Z 2 is CH.

14. The compound of claim 12 , wherein Z 2 is N and Z 1 is CH.

15. The compound of claim 1 , wherein R 2 is a substituted heteroaryl.

16. The compound of claim 1 , wherein R 2 is a substituted 6-membered heteroaryl ring containing one or two N.

17. The compound of claim 1 , wherein R 2 is selected from

each of which is substituted with one or two substituents independently selected from hydroxy, alkyl optionally substituted with alkoxy, haloalkyl, alkoxy optionally substituted with alkenyl or alkoxy, haloalkoxy, —N(R 4 ) 2 , and heteroaryl.

18. The compound of claim 1 , wherein R 2 is a substituted heterocycloalkyl or heterocycloalkenyl.

19. The compound of claim 18 , wherein R 2 is selected from

each of which is substituted with one or two substituents independently selected from hydroxy, alkyl optionally substituted with alkoxy, haloalkyl, alkoxy optionally substituted with alkenyl or alkoxy, haloalkoxy, —N(R 4 ) 2 , and heteroaryl.

20. The compound of claim 1 , wherein Z 3 is CH.

21. The compound of claim 1 , wherein X 3 is CH 2 .

22. A compound selected from

Example

Structure

1

1.1

1.2

1.3

1.4

1.5

1.6

1.8

1.10

1.11

1.12

1.13

1.14

1.15

1.16

1.17

1.18

1.19

1.20

1.21

1.22

1.23

1.24

1.25

1.26

1.27

1.28

1.29

4.3

9

15

16

20

24

24.1

24.2

24.3

24.4

25

26

28

31

34

34.1

35

35.1

36

37

38

40

41

or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

23. The compound of claim 1 , wherein the compound is labeled with one or more positron-emitting radionuclides.

24. The compound of claim 23 , wherein the compound contains one or more positron-emitting radionuclides selected from 11 C, 13 N, 15 O, and 18 F.

25. An imaging agent comprising the compound of claim 23 , or an isotopically labeled analog, pharmaceutically acceptable salt, solvate, stereoisomer, or mixture of stereoisomers thereof.

26. A method of generating diagnostic images in an individual comprising administering an effective amount of an imaging agent of claim 25 to an individual, and generating an image of a body part or body area of the individual.

27. The method of claim 26 , wherein generating an image of a body part or body area of the individual comprises generating an image to detect the presence or absence of huntingtin protein (HTT protein) in the image; and detecting the presence or absence of a pathologic process.

28. The method of claim 27 , wherein the HTT protein is found in basal ganglia.

29. The method of claim 27 , wherein the pathologic process is a neurodegenerative disease.

30. The method of claim 29 , wherein the neurodegenerative disease is selected from Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, Prion disease and spinocerebellar ataxias.

31. The method of claim 30 , wherein the neurodegenerative disease is Huntington's disease (HD).

32. The method of claim 26 , wherein the effective amount of the imaging agent comprises from about 0.1 to about 20 mCi.

33. The method of claim 32 , wherein the effective amount of the imaging agent comprises about 10 mCi.

34. The method of claim 26 , wherein 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), single-photon emission computed tomography (SPECT) imaging, or a combination thereof.

35. The method of claim 34 , wherein generating an image comprises PET imaging.

36. The method of claim 27 , wherein the HTT protein is present as aggregates thereof.

37. The method of claim 27 , wherein the HTT protein is mutant.

38. The method of claim 27 , wherein the body part or body area is selected from head, spinal cord, limb, thorax, or abdomen.

39. The method of claim 27 , wherein the body part or body area is brain.