TY - JOUR
T1 - Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-11C-methoxy]donepezil
AU - Hiraoka, Kotaro
AU - Okamura, Nobuyuki
AU - Funaki, Yoshihito
AU - Watanuki, Shoichi
AU - Tashiro, Manabu
AU - Kato, Motohisa
AU - Hayashi, Akiko
AU - Hosokai, Yoshiyuki
AU - Yamasaki, Hiroshi
AU - Fujii, Toshikatsu
AU - Mori, Etsuro
AU - Yanai, Kazuhiko
AU - Watabe, Hiroshi
N1 - Funding Information:
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) and from the Ministry of Health, as well as by a grant for ‘Molecular Imaging’ projects from the Ministry of Education, Culture, Sports, Science and Technology in Japan.
PY - 2009/7/1
Y1 - 2009/7/1
N2 - The aim of this study was to establish kinetic analysis of [5-11C-methoxy]donepezil ([11C]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 [11C]donepezil. The total distribution volume (tDV) of [11C]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 χ2 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.
AB - The aim of this study was to establish kinetic analysis of [5-11C-methoxy]donepezil ([11C]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 [11C]donepezil. The total distribution volume (tDV) of [11C]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 χ2 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.
KW - Acetylcholinesterase
KW - Acetylcholinesterase inhibitor
KW - Donepezil
KW - Positron emission tomography (PET)
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U2 - 10.1016/j.neuroimage.2009.03.006
DO - 10.1016/j.neuroimage.2009.03.006
M3 - Article
C2 - 19286462
AN - SCOPUS:64949182053
VL - 46
SP - 616
EP - 623
JO - NeuroImage
JF - NeuroImage
SN - 1053-8119
IS - 3
ER -
