title: N-[18F] fluoroethylpiperidin-4ylmethyl acetate, a novel lipophilic acetylcholine analogue for PET measurement of brain acetylcholinesterase activity.
abstract: The reduction of acetylcholinesterase (AChE) activity in the brain has been measured in dementia disorders such as Alzheimer's disease and dementia with Lewy bodies using (11)C-labeled acetylcholine analogues, N-[(11)C]methylpiperidin-4-yl acetate and propionate, and positron emission tomography (PET). Our aim was to develop an (18)F-labeled acetylcholine analogue useful for brain AChE mapping with PET, since (18)F, with a longer half-life, has advantages over (11)C. In a preliminary study, a series of N-[(14)C]ethylpiperidin-3-yl or -4-ylmethanol esters (acetyl and propionyl esters) were newly designed and evaluated in vitro regarding the reactivity with and specificity to AChE using purified human enzymes, leading to a novel (18)F-labeled acetylcholine analogue, N-[(18)F]fluoroethylpiperidin-4-ylmethyl acetate. In rat experiments, the (18)F-labeled candidate showed desirable properties for PET AChE measurement: high brain uptake of the authentic ester, high AChE specificity, a moderate hydrolysis rate, and low membrane permeability (metabolic trapping) of the metabolite.
authors.affiliation: Department of Medical Imaging, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.forename: Nobuo
authors.initials: N
authors.lastname: Ikota
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukushi
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Okamura
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Irie
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000109:Acetylcholine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D008297:Male; D008567:Membranes, Artificial; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000085:Acetates; D002800:Cholinesterase Inhibitors; D005462:Fluorine Radioisotopes; D008567:Membranes, Artificial; C500163:N-fluoroethylpiperidin-4-ylmethyl acetate; D010880:Piperidines; D019275:Radiopharmaceuticals; D000110:Acetylcholinesterase; D000109:Acetylcholine