Selective a3b4 nicotinic acetylcholine receptor ligand as a potential tracer for drug addiction

34 Nicotinic acetylcholine receptor (nAChR), a receptor involved in drug-seeking behavior, has been recognized as the emerging biomarker for early detection of the drug addiction. Herein, 34 nAChR ligands were designed and synthesized to improve binding affinity and selectivity of two lead compounds, (S)-QND8 and (S)-T2 for the development of an 34 nAChR tracer. 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 a 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 34 nAChR subtype were determined by competitive radioligand binding assay using [3H]epibatidine as a radioligand. Among all modified compounds, AK3 showed highest binding affinity and selectivity to 34 nAChR with a Ki value of 3.17 nM, comparable to (S)-QND8 and (S)-T2 and 3109-fold higher affinity to 34 nAChR in comparison to 7 nAChR. The 34 nAChR selectivity of AK3 was tremendously higher than those of (S)-QND8 (11.8-fold) and (S)-T2 (294-fold). AK3 is the promising 34 nAChR tracer for further development as a radiotracer for drug addiction.