title: Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-(11)C-methoxy]donepezil.
abstract: The aim of this study was to establish kinetic analysis of [5-(11)C-methoxy]donepezil ([(11)C]donepezil), which was developed for the in-vivo visualization of donepezil binding to acetylcholinesterase (AChE) using positron emission tomography (PET). Donepezil is an AChE inhibitor that is widely prescribed to ameliorate the cognitive impairment of patients with dementia. Six healthy subjects took part in a dynamic study involving a 60-min PET scan after intravenous injection of [(11)C]donepezil. The total distribution volume (tDV) of [(11)C]donepezil was quantified by compartmental kinetic analysis and Logan graphical analysis. A one-tissue compartment model (1TCM) and a two-tissue compartment model (2TCM) were applied in the kinetic analysis. Goodness of fit was assessed with chi(2) criterion and Akaike's Information Criterion (AIC). Compared with a 1TCM, goodness of fit was significantly improved by a 2TCM. The tDVs provided by Logan graphical analysis were slightly lower than those provided by a 2TCM. The rank order of the mean tDVs in 10 regions was in line with the AChE activity reported in a previous post-mortem study. Logan graphical analysis generated voxel-wise images of tDV, revealing the overall distribution pattern of AChE in individual brains. Significant correlation was observed between tDVs calculated with and without metabolite correction for plasma time-activity curves, indicating that metabolite correction could be omitted. In conclusion, this method enables quantitative analysis of AChE and direct investigation of the pharmacokinetics of donepezil in the human brain.
authors.affiliation: Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan. khiraoka@mail.tains.tohoku.ac.jp
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hiraoka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Okamura
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Funaki
authors.forename: Shoichi
authors.initials: S
authors.lastname: Watanuki
authors.forename: Manabu
authors.initials: M
authors.lastname: Tashiro
authors.forename: Motohisa
authors.initials: M
authors.lastname: Kato
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayashi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hosokai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Fujii
authors.forename: Etsuro
authors.initials: E
authors.lastname: Mori
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watabe
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007189:Indans / Q000493:pharmacokinetics*; D008297:Male; D010880:Piperidines / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods
chemical_list: C473648:(5-methoxy)donepezil; D000806:Angiotensin-Converting Enzyme Inhibitors; D007189:Indans; D010880:Piperidines; D000110:Acetylcholinesterase