title: (E)-[125I]-5-AOIBV: a SPECT radioligand for the vesicular acetylcholine transporter.
abstract: The premise that, over the course of Alzheimer's disease (AD), changes in the levels of the vesicular acetylcholine transporter (VAChT) occur in parallel with changes to other cholinergic marker proteins provides the basis for the applicability of benzovesamicol derivatives as radioligands for AD studies by single photon emission computed tomography or positron emission tomography. We report the synthesis of enantiopure benzovesamicol derivatives: (R,R) or (S,S)-(E)-2-hydroxy-5-(3-iodoprop-2-en-1-oxy)-3-(4-phenylpiperidino)tetralin [(R,R)-AOIBV: Kd=0.45 nM or (S,S)-5-AOIBV: Kd=4.3 nM] and their corresponding tributyltin precursors for radioiodination. (R,R or S,S)-5-AOIBV was labeled with iodine-125 from their corresponding n-tributyltin precursors. Both compounds were obtained with radiochemical and optical purity greater than 97% and in radiochemical yields ranging 34-36%. To determine if these compounds could provide an advantage when compared to [125I]-iodo benzovesamicol (IBVM), IBVM was also labeled and used as the reference compound in all ex vivo experiments. Ex vivo biodistribution experiments in rats revealed that [125I]-(R,R)-5-AOIBV displayed the most suitable pharmacological profile as the radioactivity distribution corresponded well with the known VAChT brain density. Moreover, pre-injection of vesamicol prevented the uptake of [125I]-(R,R)-5-AOIBV in striatum, cortex and hippocampus, demonstrating selectivity for the VAChT. However, even if time activity curves of [125I]-(R,R)-5-AOIBV confirmed that this compound could be used to visualize the VAChT in vivo, at each point of the kinetic study, [125I]-(R,R)-5-AOIBV showed a lower specific binding compared to [125I]-IBVM. These results made [125I]-( R,R)-5-AOIBV inferior to [125I]-IBVM for the VAChT exploration in vivo.
authors.affiliation: INSERM U619, 37000 Tours, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Zea-Ponce
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.forename: Lucette
authors.initials: L
authors.lastname: Garreau
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bodard
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Drossard
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D010880:Piperidines / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism*
chemical_list: C526996:2-hydroxy-5-(3-iodoprop-2-en-1-oxy)-3-(4-phenylpiperidino)tetralin; D010880:Piperidines; D019275:Radiopharmaceuticals; C493461:Slc18a3 protein, rat; D013764:Tetrahydronaphthalenes; D050494:Vesicular Acetylcholine Transport Proteins