Synthesis and evaluation of (鈭?- and (+)-[¹¹C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging

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• 作者：Hiroyuki Kimura ; Tomoki Kawai ; Yoshio Hamashima ; Hidekazu Kawashima ; Kenji Miura ; Yuta Nakaya ; Makoto Hirasawa ; Kenji Arimitsu ; Tetsuya Kajimoto ; Yoshiro Ohmomo ; Masahiro Ono ; Manabu Node ; Hideo Saji
• 关键词：Acetylcholinesterase inhibitor ; Galanthamine ; Positron emission tomography tracers ; C-11
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 January, 2014
• 年：2014
• 卷：22
• 期：1
• 页码：285-291
• 全文大小：817 K

文摘

Improved radiopharmaceuticals for imaging cerebral acetylcholinesterase (AChE) are needed for the diagnosis of Alzheimer鈥檚 disease (AD). Thus, ¹¹C-labeled (鈭?-galanthamine and its enantiomers were synthesized as novel agents for imaging the localization and activity of AChE by positron emission tomography (PET). C-11 was incorporated into (鈭?- and (+)-[¹¹C]galanthamine by N-methylation of norgalanthamines with [¹¹C]methyl triflate. Simple accumulation of ¹¹C in the brain was measured in an in vivo biodistribution study using mice, whilst donepezil was used as a blocking agent in analogous in vivo blocking studies. In vitro autoradiography of rat brain tissue was performed to investigate the distribution of (鈭?-[¹¹C]galanthamine, and confirmed the results of PET studies in mice. The radiochemical yields of N-methylation of (鈭?- and (+)-norgalanthamines were 13.7% and 14.4%, respectively. The highest level of accumulation of ¹¹C in the brains of mice was observed at 10 min after administration (2.1% ID/g). Intravenous pretreatment with donepezil resulted in a 30% decrease in accumulation of (鈭?-[¹¹C]galanthamine in the striatum; however, levels in the cerebellum were unchanged. In contrast, use of (+)-[¹¹C]galanthamine led to accumulation of radioactivity in the striatum equal to that in the cerebellum, and these levels were unaffected by pretreatment with donepezil. In in vitro autoradiography of regional radioactive signals of brain sections showed that pretreatment with either (鈭?-galanthamine or donepezil blocked the binding of (鈭?-[¹¹C]galanthamine to the striatum, while sagittal PET imaging revealed accumulation of (鈭?-[¹¹C]galanthamine in the brain. These results indicate that (鈭?-[¹¹C]galanthamine showed specific binding to AChE, whereas (+)-[¹¹C]-galanthamine accumulated in brain tissue by non-specific binding. Thus, optically pure (鈭?-[¹¹C]galanthamine could be a useful PET tracer for imaging cerebral AChE.