First CoMFA Characterization of Vesamicol Analogs as Ligands for the Vesicular Acetylcholine Transporter

Vesamicol derivatives are promising candidates as ligands for the vesicular acetylcholine transporter (VAChT) to enable in vivo imaging of cholinergic deficiencies if applied as positron emission tomography radiotracers. So far, optimization of the binding affinity of vesamicol-type ligands was hampered by the lack of respective quantitative structure–activity relationships. We developed the first quantitative model to predict, from molecular structure, the binding affinity of vesamicol-type ligands toward VAChT employing comparative molecular field analysis (CoMFA) for a set of 37 ligands, covering three different structural types (4-phenylpiperidine, spiro, and tropan derivatives of vesamicol). The prediction capability was assessed by leave-one-out cross-validation (LOO) and through leaving out and predicting 50% of the compounds selected such that both the training and the prediction sets cover almost the whole range of experimental data. The statistics indicate a significant prediction power of the models (q² (LOO) = 0.66, q² (50% out) = 0.59–0.74). The discussion includes detailed analyses of CoMFA regions critical for ligand−VAChT binding, identifying structural implications for high binding affinity.