Alpha-synuclein ligands
The present invention generally relates to various compounds that are useful as α-synuclein ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of synucleinopathies, including Parkinson's disease (PD).
1. A compound having the structure of Formula (III-A):
wherein A 11 is C—R 11 or nitrogen; A 12 is C—R 12 or nitrogen; A 13 is C—R 13 or nitrogen; A 14 is C—R 14 ; A 15 is C—R 15 or nitrogen and at least one of A 11 , A 12 , A 13 , or A 15 is nitrogen;
R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 20 , and R 21 are independently hydrogen, nitro, halo, hydroxy, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted amino, or substituted or unsubstituted amido;
R 14 is nitro, halo, hydroxy, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted amino, or substituted or unsubstituted amido; and
R 19 is nitro, halo, hydroxy, carboxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxylate, substituted or unsubstituted amino, or substituted or unsubstituted amido, and
wherein the compound is radiolabeled with a synthetic radioactive isotope.
2. A compound selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
3. The compound of claim 2 wherein the compound is radiolabeled with a synthetic radioactive isotope.
4. The compound of claim 3 wherein the synthetic radioactive isotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18, bromine-76, iodine-123, and iodine-125.
5. A pharmaceutical composition comprising a radiolabeled compound of claim 1 and at least one excipient.
6. A pharmaceutical composition comprising a compound of claim 1 wherein the composition comprises from about 0.001 mg to about 10 g of the compound and at least about 10 wt. % of the compound in the pharmaceutical composition is radiolabeled.
7. A method of diagnosing or monitoring a synucleinopathy in a human subject comprising administering a pharmaceutical composition comprising a compound of claim 1 to a human subject; and imaging the subject's brain by positron emission tomography.
8. The compound of claim 1 wherein A 13 is nitrogen.
9. The compound of claim 1 wherein A 11 is C—R 11 ; A 12 is C—R 12 ; and A 15 is C—R 15 .
10. The compound of claim 8 wherein A 11 is C—R 11 ; A 12 is C—R 12 ; and A 15 is C—R 15 .
11. The compound of claim 1 wherein R 11 , R 12 , R 13 , R 15 , R 16 , R 17 , R 18 , R 20 , and R 21 are independently hydrogen, nitro, halo, hydroxy, carboxyl, C 1 to C 6 alkyl, halo-substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, halo-substituted C 1 to C 6 alkoxy, amino, C 1 to C 6 alkyl-substituted amino, amido, C 1 to C 6 alkyl-substituted amido, C 1 to C 6 alkyl-substituted carboxylate, or C 1 to C 6 haloalkyl-substituted carboxylate.
12. The compound of claim 1 wherein R 14 and R 19 are independently nitro, halo, hydroxy, carboxyl, C 1 to C 6 alkyl, halo-substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, halo-substituted C 1 to C 6 alkoxy, amino, C 1 to C 6 alkyl-substituted amino, amido, C 1 to C 6 alkyl-substituted amido, C 1 to C 6 alkyl-substituted carboxylate, or C 1 to C 6 haloalkyl-substituted carboxylate.
13. The compound of claim 1 wherein R 14 and R 19 are independently nitro, halo, hydroxy, carboxyl, C 1 to C 6 alkyl, halo-substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, or halo-substituted C 1 to C 6 alkoxy.
14. The compound of claim 1 wherein R 19 is halo, C 1 to C 6 alkyl, halo-substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, or halo-substituted C 1 to C 6 alkoxy.
15. The compound of claim 1 wherein R 14 is C 1 to C 6 alkyl or C 1 to C 6 alkoxy.
16. The compound of claim 14 wherein R 14 is C 1 to C 6 alkyl or C 1 to C 6 alkoxy.
17. The compound of claim 1 wherein each of R 16 , R 17 , R 18 , R 20 , and R 21 is hydrogen.
18. The compound of claim 1 wherein at least two of A 11 , A 12 , A 13 , A 15 are each nitrogen.
19. The compound of claim 1 wherein the synthetic radioactive isotope is selected from the group consisting of carbon-11, nitrogen-13, oxygen-15, fluorine-18, bromine-76, iodine-123, and iodine-125.
20. A method of diagnosing or monitoring a synucleinopathy in a human subject comprising administering a pharmaceutical composition comprising a compound of claim 3 to a human subject; and imaging the subject's brain by positron emission tomography.