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タイトル: Synthesis and evaluation of (-)- and (+)-[(11)C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging.
著者: Kimura, Hiroyuki  KAKEN_id
Kawai, Tomoki
Hamashima, Yoshio
Kawashima, Hidekazu
Miura, Kenji
Nakaya, Yuta
Hirasawa, Makoto
Arimitsu, Kenji
Kajimoto, Tetsuya
Ohmomo, Yoshiro
Ono, Masahiro  kyouindb  KAKEN_id
Node, Manabu
Saji, Hideo  kyouindb  KAKEN_id
著者名の別形: 木村, 寛之
佐治, 英郎
キーワード: Acetylcholinesterase inhibitor
Galanthamine
Positron emission tomography tracers
C-11
発行日: 1-Jan-2014
出版者: Elsevier Ltd.
誌名: Bioorganic & medicinal chemistry
巻: 22
号: 1
開始ページ: 285
終了ページ: 291
抄録: Improved radiopharmaceuticals for imaging cerebral acetylcholinesterase (AChE) are needed for the diagnosis of Alzheimer's disease (AD). Thus, (11)C-labeled (-)-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 (-)- and (+)-[(11)C]galanthamine by N-methylation of norgalanthamines with [(11)C]methyl triflate. Simple accumulation of (11)C 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 (-)-[(11)C]galanthamine, and confirmed the results of PET studies in mice. The radiochemical yields of N-methylation of (-)- and (+)-norgalanthamines were 13.7% and 14.4%, respectively. The highest level of accumulation of (11)C in the brains of mice was observed at 10min after administration (2.1% ID/g). Intravenous pretreatment with donepezil resulted in a 30% decrease in accumulation of (-)-[(11)C]galanthamine in the striatum; however, levels in the cerebellum were unchanged. In contrast, use of (+)-[(11)C]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 (-)-galanthamine or donepezil blocked the binding of (-)-[(11)C]galanthamine to the striatum, while sagittal PET imaging revealed accumulation of (-)-[(11)C]galanthamine in the brain. These results indicate that (-)-[(11)C]galanthamine showed specific binding to AChE, whereas (+)-[(11)C]-galanthamine accumulated in brain tissue by non-specific binding. Thus, optically pure (-)-[(11)C]galanthamine could be a useful PET tracer for imaging cerebral AChE.
著作権等: © 2013 Published by Elsevier Ltd.
This is not the published version. Please cite only the published version. この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。
URI: http://hdl.handle.net/2433/180294
DOI(出版社版): 10.1016/j.bmc.2013.11.026
PubMed ID: 24315193
出現コレクション:学術雑誌掲載論文等

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