Acetylene derivatives and their use for binding and imaging amyloid plaques

1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein:

A 1 is CH

A 2 is CH or N;

R 1 and R 2 are each independently:

hydrogen, —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NH 2 , C 1-4 alkoxy or —OH;

R 3 fragment i, ii or iii, wherein:

fragment i is:

wherein n is an integer from 1 to 10; m is an integer from 0 to 5; y is an integer from 0 to 5;

R 5 is hydrogen, C 1-4 alkyl, or hydroxy(C 1-4 )alkyl; R a , R b , R c , R d , R e , R f , R g and R h are each independently hydrogen, halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, or hydroxy(C 1-4 )alkyl; and

Z is:

a) X, wherein X is hydrogen, hydroxy, halogen, radiohalogen, C 1-4 alkoxy, hydroxy(C 1-4 )alkyl, halo(C 1-4 )alkyl, radiohalo(C 1-4 )alkyl or NR x R y , wherein R x and R y are independently hydrogen, C 1-4 alkyl, hydroxy(C 1-4 )alkyl, radiohalo(C 1-4 )alkyl or halo(C 1-4 )alkyl;

b) one of the following groups, each of which contains X as a substituent:

benzoyloxy, phenyl(C 1-4 )alkyl, aryloxy or C 6-10 aryl;

or

c) Zc, having the following structure:

wherein p is an integer from 1 to 4, Q is O or NR 5 and G is —C═C—(R G )X or —C≡C—X, wherein R G is hydrogen or C 1-4 alkyl, and R n and R o are independently hydrogen, hydroxyl or C 1-4 alkyl;

fragment ii is:

wherein y′is an integer from 0 to 5;

and fragment iii is:

wherein e is 0 or 1;

R 4 is hydrogen, halogen, or radiohalogen;

provided that,

if X is not or does not contain F or 18 F, then R 4 is F, 18 F 123 I, 125 I, 131 I, 76 Br, or 77 Br or Br.

2. The compound of claim 1 , wherein R 2 is hydrogen.

3. The compound of claim 1 , wherein A 2 is N.

4. The compound of claim 1 , wherein A 2 is CH.

5. The compound of claim 1 , wherein R 3 is

wherein

y is an integer from 1 to 5.

6. The compound of claim 5 , wherein:

n is an integer from 1 to 6;

m is an integer from 0 to 3; and

y is an integer from 1 to 3.

7. The compound of claim 6 , wherein:

n is an integer from 2 to 6;

m is 0; and

y is 2.

8. The compound of claim 5 , wherein R a , R b , R c , R d , R e , R f , R g and R h are each hydrogen.

9. The compound of claim 5 that is:

wherein

n is an integer from 1 to 6;

and

X is hydrogen, halogen, radiohalogen, C 1-4 alkoxy, hydroxy or NR x R Y ; provided that,

X is or contains 18 F or R 4 is 123 I, 125 I, or 131 I.

10. The compound of claim 9 , wherein:

n is 3;

R 1 is hydroxy, —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , or —NH 2 ;

and

X is hydroxy, halogen or radiohalogen.

11. The compound of claim 1 , wherein R 3 is

provided that,

X is 18 F or R 4 is 123 I, 125 I or 131 I.

12. The compound of claim 1 that is:

wherein

n is an integer from 2 to 6;

and

X is hydroxy, halogen or radiohalogen;

provided that,

X is 18 F or R 4 is 123 I, 125 I or 131 I.

13. The compound of claim 12 , wherein A 2 is N.

14. The compound of claim 12 , wherein R a , R b , R c and R d are hydrogen.

15. The compound of claim 12 , wherein n is 3.

16. The compound of claim 1 , wherein R 3 is

provided that,

X is or contains 18 F or R 4 is 123 I, 125 I or 131 I.

17. The compound of claim 16 , wherein e is 1.

18. The compound of 17 , wherein:

Z is:

X, wherein X is hydrogen, halogen, radiohalogen, C 1-4 alkoxy, hydroxy or NR′R″; or

Zc, having the following structure:

19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

20. A diagnostic composition for imaging amyloid deposits, comprising a radiolabeled compound of claim 1 and a pharmaceutically acceptable excipient.

21. A method of imaging amyloid deposits in a patient, comprising:

a. introducing into the patient a detectable quantity of a diagnostic composition of claim 20 ;

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.

22. The compound of claim 1 that is

23. The compound of claim 1 that is

24. The compound of claim 1 that is