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

α[sub.3]β[sub.4] Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α[sub.3]β[sub.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[sub.3]β[sub.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[sub.3]β[sub.4] nAChR subtype, were determined by competitive radioligand binding assay using [[sup.3]H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α[sub.3]β[sub.4] nAChR with a Ki value of 3.18 nM, comparable to (S)-QND8 and (S)-T2 and 3069-fold higher affinity to α[sub.3]β[sub.4] nAChR in comparison to α[sub.7] nAChR. The α[sub.3]β[sub.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[sub.3]β[sub.4] nAChR tracer for further development as a radiotracer for drug addiction.