title: Ex vivo and in vivo evaluation of (2R,3R)-5-[(18)F]-fluoroethoxy- and fluoropropoxy-benzovesamicol, as PET radioligands for the vesicular acetylcholine transporter.
abstract: Molecular imaging of the vesicular acetylcholine transporter (VAChT) using positron emission tomography (PET) may provide insights into early diagnosis and better understanding of Alzheimer's disease. We further characterized the VAChT ligand (2R,3R)-5-FEOBV (1) and developed new fluoropropoxy analogues. Ex vivo studies of the new nonradiolabeled analogues (2R,3R)-5-FPOBV (2) (k(D) = 0.7 nM) and (2S,3S)-5-FPOBV (3) (k(D) = 8.8 nM) were performed in rat brain and showed an enantioselective inhibition of (-)-5-[(125)I]-IBVM uptake in striatum, cortex, and hippocampus (e.g., 74% for 2 and only 54% for 3 in the cortex). Radiochemical procedures were developed to produce [(18)F]1 and [(18)F]2 as potential imaging agent for the VAChT. The radiochemistry was carried out in a one step procedure, with radiolabeling yields of 17 and 2.6% (range: 1-5.4), respectively, nondecay corrected with good specific activity: 124-338 GBq/micromol. The radiochemical purity was greater than 98%. The biological (ex vivo and in vivo) properties of these radioligands were evaluated in rats and showed a low (less then 0.1% of the injected dose) and homogeneous brain uptake. The in vivo PET study of [(18)F]2 performed in baboon also revealed rapid defluorination as the main problem. Therefore [(18)F]1 and [(18)F]2 appear to be unsuitable for in vivo imaging of the VAChT using PET.
authors.affiliation: Inserm, U619, 37000 Tours, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Giboureau
authors.forename: Patrick
authors.initials: P
authors.lastname: Emond
authors.forename: Roger R
authors.initials: RR
authors.lastname: Fulton
authors.forename: David J
authors.initials: DJ
authors.lastname: Henderson
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chalon
authors.forename: Lucette
authors.initials: L
authors.lastname: Garreau
authors.forename: Peter
authors.initials: P
authors.lastname: Roselt
authors.forename: Stefan
authors.initials: S
authors.lastname: Eberl
authors.forename: Sylvie
authors.initials: S
authors.lastname: Mavel
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bodard
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fulham
authors.forename: Denis
authors.initials: D
authors.lastname: Guilloteau
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005069:Evaluation Studies as Topic; D007553:Isotope Labeling; D008297:Male; D010215:Papio; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D050494:Vesicular Acetylcholine Transport Proteins / Q000032:analysis*; D051598:Whole Body Imaging