Sulfur-containing compounds targeting vesicular acetylcholine transporter
The present invention generally relates to various compounds that are useful as vesicular acetylcholine transporter (VAChT) ligands. The invention further relates to methods of using these compounds and their radiolabeled analogs for the detection of neurodegenerative diseases including Parkinson's disease (PD), and Alzheimer's disease (AD).
1. A compound having a structure of Formula I, or a salt thereof:
wherein R 1 , R 2 , and R 3 are each independently hydrogen, C 1 -C 6 alkyl, or
and at least one of R 1 , R 2 , and R 3 is
R 4 is a substituted or unsubstituted C 1 -C 6 alkyl; substituted or unsubstituted amino;
m is 0, 1 or 2; and
n is 0 or 1.
2. The compound of claim 1 wherein at least two of R 1 , R 2 , and R 3 are hydrogen.
3. The compound of claim 1 wherein R 2 and R 3 are each hydrogen.
4. The compound of claim 1 wherein R 4 is a C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkylamino, substituted or unsubstituted C 1 -C 6 haloalkyl.
5. The compound of claim 1 wherein R 4 is a methyl, ethyl, propyl, butyl, fluoroethyl, fluoropropyl, methylamino, ethylamino, fluoroethylamino, or fluoropropylamino.
6. The compound of claim 1 wherein Formula I has the structure of Formula II, or salt thereof:
wherein R 1 , R 2 , and R 3 are as defined above.
7. The compound of claim 1 wherein Formula I has a structure selected from the group consisting of:
stereoisomers or salts thereof, and mixtures thereof.
8. The compound of claim 1 wherein Formula I has a structure selected from the group consisting of:
stereoisomers or salts thereof, and mixtures thereof.
9. The compound of claim 1 wherein Formula I has a structure selected from the group consisting of:
salts thereof, and mixtures thereof.
10. The compound of claim 1 wherein the compound is radiolabeled with a synthetic radioactive isotope.
11. The compound of claim 10 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.
12. The compound of claim 11 wherein the radiolabeled compound is selected from a group consisting of:
salts thereof, and mixtures thereof.
13. A pharmaceutical composition comprising a radiolabeled compound of claim 10 .
14. A pharmaceutical composition comprising a compound of claim 10 wherein the composition comprises from about 0.001 mg to about 10 g of the compound and at least about 10 wt. %, at least about 25 wt. %, at least about 50 wt. %, at least about 75 wt. %, at least about 90 wt. %, or at least about 95 wt. % of the compound in the pharmaceutical composition is radiolabeled.
15. A method of diagnosing or monitoring a neurodegenerative disease in a mammal comprising administering a composition comprising a compound of claim 10 to the mammal; and imaging the mammal's brain by positron emission tomography.
16. A method of quantifying vesicular acetylcholine transporter (VAChT) in a mammal comprising administering a composition comprising a compound of claim 10 to the mammal; and imaging the mammal's brain by positron emission tomography.
17. The method of claim 15 wherein the neurodegenerative disease comprises Parkinson's Disease or Alzheimer's Disease.
18. The method of claim 15 wherein the mammal is a human.
19. The method of claim 17 wherein the mammal is a human.
20. The method of claim 16 wherein the mammal is a human.