Styrylpyridine derivatives and their use for binding and imaging amyloid plaques

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof; wherein

n is an integer from one to six;

A 4 is N;

A 1 , A 2 , A 3 , and A 5 are independently —CH, or —CR 2 , as permitted;

R 1 is:

—(CH 2 ) p NR a R b , wherein R a and R b are independently hydrogen, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl hydroxy(C 1-4 )alkyl or halo(C 1-4 )alkyl, and p is an integer from 0 to 5;

hydroxy,

(C 1-4 ) alkoxy,

hydroxy(C 1-4 )alkyl,

halogen,

cyano,

nitro,

(C 1-4 )alkyl,

halo(C 1-4 )alkyl,

formyl,

—NHCO(C 1-4 alkyl), or

—OCO(C 1-4 alkyl);

R 2 is:

wherein, q is an integer from 1 to 10, Rx and Ry are hydrogen, hydroxy or C 1-4 alkyl; t is 0, 1, 2 or 3; Z is hydroxy, halogen, benzoyloxy substituted with halogen, benzyloxy substituted with halogen, phenyl(C 1-4 )alkyl substituted with halogen, aryloxy substituted with halogen, or a C 6-10 aryl substituted with halogen; and R 30 , R 31 , R 32 and R 33 are in each instance independently hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or hydroxy(C 1-4 alkyl;

wherein Rx and Ry are hydrogen, hydroxy or C 1-4 alkyl; t is 0, 1, 2 or 3;

Y is halogen, benzoyloxy substituted with halogen, phenyl(C 1-4 )alkyl substituted with halogen, aryloxy substituted with halogen, or C 6-10 aryl substituted with halogen;

U is hydrogen, hydroxy, halogen, benzoyloxy substituted with halogen, phenyl(C 1-4 )alkyl substituted with halogen, aryloxy substituted with halogen, or C 6-10 aryl substituted with halogen; and

R 34 , R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are in each instance independently hydrogen, halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or hydroxy(C 1-4 )alkyl;

iii. NR′R″, wherein at least one of R′ and R″ is (CH 2 ) d X, where X is halogen, and d is an integer from 1 to 4; the other of R′ and R″ is hydrogen, C 1-4 -alkyl, halo(C 1-4 )alkyl, or hydroxy(C 1-4 alkyl;

iv. halo(C 1-4 )alkyl; or

v. an ether having the structure: [halo(C 1-4 )alkyl-O—(C 1-4 )alkyl]-; and

R 7 and R 8 are each hydrogen.

2. The compound of claim 1 wherein

R 1 is hydroxy or —(CH 2 ) p NR a R b , wherein p is an integer from 0 to 5, and R a and R b are each independently hydrogen, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, or (CH 2 ) d X, where X is halogen, and d is an integer from 1 to 4,

R 2 is

wherein t is 0;

wherein t is 0;

iii. NR′R″;

iv. halo(C 1-4 )alkyl; or

v. an ether having the structure: [halo(C 1-4 )alkyl-O—(C 1-4 )alkyl]-.

3. The compound of claim 1 , wherein n is one.

4. The compound of claim 1 , wherein at least one halogen is a radiohalogen.

5. The compound of claim 1 , wherein at least one halogen is I, 123 I, 125 I, 131 I, 76 Br, 77 Br, F or 18 F.

6. The compound of claim 5 , wherein R 1 is —(CH 2 ) p NR a R b , wherein R a and R b are each independently hydrogen, ethyl, propyl, isopropyl, butyl, or t-butyl, isobutyl and p is 0.

7. The compound of claim 6 , wherein R 2 is

wherein t is 0.

8. The compound of claim 7 , wherein q is an integer from 1 to 5.

9. The compound of claim 8 , wherein R 30 , R 31 , R 32 and R 33 are each hydrogen.

10. The compound of claim 9 , having the formula:

wherein, R a and R b are each independently hydrogen, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl and Z is I, 123 I, 125 I, 131 I, Br, 76 Br, 77 Br, F or 18 F.

11. The compound of claim 6 , wherein R 2 is

wherein t is 0 and Z is hydroxy.

12. The compound of claim 11 , wherein q is an integer from 1 to 5.

13. The compound of claim 12 , wherein R 30 , R 31 , R 32 and R 33 are each hydrogen, and q is 1, 2 or 3.

14. The compound of claim 6 , wherein R 2 is

wherein t is 0 and U is hydroxy.

15. The compound of claim 14 , wherein R 34 , R 35 , R 36 and R 37 , R 38 , R 39 and R 40 are each hydrogen.

16. The compound of claim 14 , having the formula:

wherein R a and R b are each independently hydrogen, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl.

17. A composition comprising a compound according to claim 1 wherein said compound comprises a 11 C isotope, said isotope present in an amount above natural abundance, and said compound containing said 11 C isotope having a specific activity above background level.

18. A compound of Formula Ia:

wherein A 4 is N and A 1 , A 2 , A 3 , and A 5 are —CH or C—(O—CH 2 CH 2 ) q X as permitted; q is an integer from 1 to 10; R′ and R″ are each independently hydrogen, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl and X is a radiohalogen.

19. The compound of claim 18 , wherein one of R′ and R″ is hydrogen, the other is ethyl, propyl, isopropyl, butyl, t-butyl or isobutyl.

20. A pharmaceutical composition comprising a compound of any one of claim 1 or 18 and a pharmaceutically acceptable carrier or diluent.

21. A diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of any one of claim 1 or 18 and a pharmaceutically acceptable carrier or diluent.

22. A method of imaging amyloid deposits in a mammal, comprising:

a. introducing into the mammal a detectable quantity of a diagnostic composition of claim 21 ;

b. allowing sufficient time for the labeled compound to be associated with amyloid deposits; and

c. detecting the labeled compound associated with one or more amyloid deposits.