Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-11C-methoxy]donepezil
Quantitative analysis of donepezil binding to acetylcholinesterase using positron emission tomography and [5-11C-methoxy]donepezil
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DOI：
10.1016/j.neuroimage.2009.03.006
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发表时间：
2009-07-01
期刊：
影响因子：
5.7
通讯作者：
Watabe, Hiroshi
中科院分区：
文献类型：
--
作者：
Hiraoka, Kotaro;Okamura, Nobuyuki;Watabe, Hiroshi
本研究的目的是建立[5-(11)C-甲氧基多奈哌齐（[(11)C]多奈哌齐）的动力学分析，该分析是为使用正电子发射断层扫描（PET）对多奈哌齐与乙酰胆碱酯酶（AChE）结合的体内可视化而开发的。多奈哌齐是一种乙酰胆碱酯酶抑制剂，广泛用于改善痴呆症患者的认知障碍。六名健康受试者参加了一项动态研究，该研究涉及静脉注射[(11)C]多奈哌齐后进行 60 分钟的 PET 扫描。 [(11)C]多奈哌齐的总分布体积(tDV)通过区室动力学分析和Logan图分析进行量化。动力学分析采用单组织室模型（1TCM）和二组织室模型（2TCM）。使用chi(2) 标准和Akaike 信息标准(AIC) 评估拟合优度。与 1TCM 相比，2TCM 的拟合优度显着提高。 Logan 图形分析提供的 tDV 略低于 2TCM 提供的 tDV。 10 个区域的平均 tDV 的排名顺序与之前尸检研究中报告的 AChE 活性一致。 Logan 图形分析生成了 tDV 的体素图像，揭示了 AChE 在个体大脑中的总体分布模式。在对血浆时间-活性曲线进行和不进行代谢物校正的情况下计算的 tDV 之间观察到显着相关性，表明可以省略代谢物校正。总之，该方法能够定量分析 AChE 并直接研究多奈哌齐在人脑中的药代动力学。 (C) 2009 Elsevier Inc. 保留所有权利。
The aim of this study was to establish kinetic analysis of [5-(11)C-methoxyldonepezil ([(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. (C) 2009 Elsevier Inc. All rights reserved.