title: Evaluation of the binding characteristics of [5-(11)C-methoxy]Donepezil in the rat brain for in vivo visualization of acetylcholinesterase.
abstract: Donepezil, an acetylcholinesterase (AChE) inhibitor, has not been evaluated for its binding characteristics using a radioactive tracer, although its inhibitory action on AChE has been studied. The aim of this research is to examine whether AChE can be visualized in vivo and in vitro with [(11)C]donepezil. [5-(11)C-methoxy]Donepezil was synthesized by O-methylation using [(11)C]methyl triflate. The binding of [(11)C]donepezil to brain homogenates was higher in the brain stem and striatum, and it was lowest in the cerebellum. The in vitro autoradiographic study successfully demonstrated the specific binding of [(11)C]donepezil to AChE in the rat brain. The IC(50) value of binding was approximately 10 nM, which is comparable to the reported value for inhibiting enzyme activity (6 nM). Saturation experiments revealed that the B(max) and K(d) of [(11)C]donepezil binding in vitro are 65 fmol/mg tissue and 39.8 nM, respectively. In accordance with the in vitro bindings, the in vivo distribution of [(11)C]donepezil was heterogeneous in the rat brain. In the blocking experiments, the heterogeneous distribution disappeared in the presence of a large amount of unlabeled donepezil. These data suggest that [5-(11)C-methoxy]donepezil can be potentially useful to image AChE non-invasively in the human brain by positron emission tomography.
authors.affiliation: Cyclotron and Radioisotope Center, Tohoku University, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Funaki
authors.forename: Motohisa
authors.initials: M
authors.lastname: Kato
authors.forename: Ren
authors.initials: R
authors.lastname: Iwata
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakurai
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sakurai
authors.forename: Manabu
authors.initials: M
authors.lastname: Tashiro
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ido
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology; D001923:Brain Chemistry / Q000502:physiology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D000077265:Donepezil; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C473648:(5-methoxy)donepezil; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D019275:Radiopharmaceuticals; D000077265:Donepezil; D000110:Acetylcholinesterase