3D QSAR study, synthesis, and in vitro evaluation of (+)-5-FBVM as potential PET radioligand for the vesicular acetylcholine transporter (VAChT) |
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Authors: | Kovac Mitja Mavel Sylvie Deuther-Conrad Winnie Méheux Nathalie Glöckner Jana Wenzel Barbara Anderluh Marko Brust Peter Guilloteau Denis Emond Patrick |
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Institution: | 1. Université François-Rabelais de Tours, INSERM U930, CHRU, Hôpital Bretonneau, Service de Médecine Nucléaire, 37000 Tours, France;2. Forschungszentrum Dresden-Rossendorf, Research Site Leipzig, Institute of Radiopharmacy, Permoserstr. 15, 04318 Leipzig, Germany;3. University of Ljubljana, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, A?ker?eva 7, 1000 Ljubljana, Slovenia |
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Abstract: | Located in presynaptic cholinergic nerve terminals, the vesicular acetylcholine transporter (VAChT) represents a potential target for quantitative visualization of early degeneration of cholinergic neurons in Alzheimer's disease using PET. Benzovesamicol derivatives are proposed as radioligands for this purpose. We report QSAR studies of vesamicol and benzovesamicol derivatives taking into account the stereoselectivity of the VAChT binding site. Use of different data sets and different models in this study revealed that both enantiomers of 5-fluoro-3-(4-phenyl-piperidin-1-yl)-1,2,3,4-tetrahydro-naphthalen-2-ol (5-FBVM) are promising candidates, with predicted VAChT affinities between 6.1 and 0.05 nM. The synthesis of enantiopure (R,R)- and (S,S)-5-FBVM and their corresponding triazene precursors for future radiofluorination is reported. Both enantiomers exhibited high in vitro affinity for VAChT (+)-5-FBVM: K(i)=6.95 nM and (-)-5-FBVM: K(i)=3.68 nM] and were selective for σ(2) receptors (~70-fold), only (+)-5-FBVM is selective for σ(1) receptors (~fivefold). These initial results suggest that (+)-(S,S)-5-FBVM warrants further investigation as a potential radioligand for in vivo PET imaging of cholinergic nerve terminals. |
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