Selective α3β4 Nicotinic Acetylcholine Receptor Ligand as a Potential Tracer for Drug Addiction

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

Automated summary

In this study, alpha(3)beta(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 alpha(3)beta(4) nAChR tracer. AK3 showed the highest binding affinity and selectivity to alpha(3)beta(4) nAChR, making it a promising tracer for drug addiction. The structural modification included retaining key features, expanding the molecular structure, and introducing a benzyloxy group for increased lipophilicity and extended ligand-receptor interaction.