Labeled ALPHA4BETA2 ligands and methods therefor
Contemplated compositions and methods are employed to bind in vitro and in vivo to an α4β2 nicotinic acetylcholine receptor in a highly selective manner. Where such compounds are labeled, compositions and methods employing such compounds can be used for PET and SPECT analysis. Alternatively, and/or additionally contemplated compounds can be used as antagonists, partial agonists or agonists in the treatment of diseases or conditions associated with α4ββ2 dysfunction.
1. A compound according to Formula I
in which X is CH═CH, CH═N, N═CH, O, S, or NR 3 , where R 3 is hydrogen or lower alkyl;
Y is O, S, or NR 3 ;
is a double bond;
Q is lower alkyl;
R 1 is selected from the group consisting of hydrogen, halogen, halogen isotope, O-toluenesulfonyl, trialkyltin, and trialkylamine; or Q and R 1 taken together are null where n is 1 or 2;
Z is independently halogen, halogen isotope, NO 2 , or trialkylamine;
m is 1 and n is independently 0 to 3, inclusive; and
R 2 is selected from the group consisting of hydrogen, lower alkyl, and a butoxycarbonyl group.
2. The compound according to claim 1 wherein X is —CH═N—, Y is O, R 2 is hydrogen or alkyl, Q is propyl, m is 1 and n is 0, and wherein R 1 is fluoride or radiolabeled fluoride.
3. The compound of claim 1 wherein X is —CH═N—, Y is O, R 2 is hydrogen or alkyl, Q and R 1 taken together are null, and wherein n is 1 or 2.
4. The compound of claim 1 having a structure according to Formula II
wherein R 1 ′ and R 1 ″ are independently defined as R 1 ;
with the proviso that where R 1 ′ and R 1 ″ are hydrogen R 1 is not halogen.
5. The compound of claim 1 having a structure according to Formula IV
6. The compound of claim 1 having a structure according to Formula VI
7. The compound of claim 1 having a structure according to Formula VII
8. The compound of claim 1 having a structure according to Formula VIII