Selective α 3 β 4 Nicotinic Acetylcholine Receptor Ligand as a Potential Tracer for Drug Addiction.

α 3 β 4 Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α 3 β 4 nAChR ligands were designed and synthesized to improve the binding affinity and selectivity of two lead compounds, ( S ) - QND8 and ( S ) - T2 , for the development of an α 3 β 4 nAChR tracer. The structural modification was achieved by retaining the key features and expanding the molecular structure with a benzyloxy group to increase the lipophilicity for blood-brain barrier penetration and to extend the ligand-receptor interaction. The preserved key features are a fluorine atom for radiotracer development and a p -hydroxyl motif for ligand-receptor binding affinity. Four ( R )- and ( S )-quinuclidine-triazole ( AK1 - AK4 ) were synthesized and the binding affinity, together with selectivity to α 3 β 4 nAChR subtype, were determined by competitive radioligand binding assay using [ 3 H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α 3 β 4 nAChR with a K i value of 3.18 nM, comparable to ( S ) - QND8 and ( S ) - T2 and 3069-fold higher affinity to α 3 β 4 nAChR in comparison to α 7 nAChR. The α 3 β 4 nAChR selectivity of AK3 was considerably higher than those of ( S ) - QND8 (11.8-fold) and ( S ) - T2 (294-fold). AK3 was shown to be a promising α 3 β 4 nAChR tracer for further development as a radiotracer for drug addiction.