title: 3D QSAR study, synthesis, and in vitro evaluation of (+)-5-FBVM as potential PET radioligand for the vesicular acetylcholine transporter (VAChT).
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.
authors.affiliation: Université François-Rabelais de Tours, INSERM U930, CHRU, Hôpital Bretonneau, Service de Médecine Nucléaire, 37000 Tours, France.
authors.forename: Mitja
authors.initials: M
authors.lastname: Kovac
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.forename: Nathalie
authors.initials: N
authors.lastname: Méheux
authors.forename: Jana
authors.initials: J
authors.lastname: Glöckner
authors.forename: Barbara
authors.initials: B
authors.lastname: Wenzel
authors.forename: Marko
authors.initials: M
authors.lastname: Anderluh
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
mesh_terms: D001665:Binding Sites; D008024:Ligands; D009284:Naphthols / Q000138:chemical synthesis / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry*; D049268:Positron-Emission Tomography; D021281:Quantitative Structure-Activity Relationship; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism; D050494:Vesicular Acetylcholine Transport Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: C555727:5-fluoro-3-(4-phenylpiperidin-1-yl)-1,2,3,4-tetrahydronaphthalen-2-ol; D008024:Ligands; D009284:Naphthols; D010880:Piperidines; D019275:Radiopharmaceuticals; D050494:Vesicular Acetylcholine Transport Proteins; C502757:benzovesamicol; C006189:vesamicol