title: Synthesis and evaluation of (-)- and (+)-[¹¹C]galanthamine as PET tracers for cerebral acetylcholinesterase imaging.
abstract: 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 10 min 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.
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hkimura@pharm.kyoto-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Kimura
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Tomoki
authors: T
authors: Kawai
authors: Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Yoshio
authors: Y
authors: Hamashima
authors: Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Hidekazu
authors: H
authors: Kawashima
authors: SHI Accelerator Service Ltd, 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
authors: Kenji
authors: K
authors: Miura
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Yuta
authors: Y
authors: Nakaya
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Makoto
authors: M
authors: Hirasawa
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Kenji
authors: K
authors: Arimitsu
authors: Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Tetsuya
authors: T
authors: Kajimoto
authors: Osaka University of Pharmaceutical Sciences, 4-1-20 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors: Yoshiro
authors: Y
authors: Ohmomo
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Masahiro
authors: M
authors: Ono
authors: Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono-cho, Yamashina-ku, Kyoto 607-8414, Japan.
authors: Manabu
authors: M
authors: Node
authors: Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hsaji@pharm.kyoto-u.ac.jp.
authors: Hideo
authors: H
authors: Saji
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D005702:Galantamine / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D014018:Tissue Distribution
chemical_list: D002800:Cholinesterase Inhibitors; D005702:Galantamine; D000110:Acetylcholinesterase
keywords: Acetylcholinesterase inhibitor; C-11; Galanthamine; Positron emission tomography tracers