N-[18F] fluoroethylpiperidin-4ylmethyl acetate, a novel lipophilic acetylcholine analogue for PET measurement of brain acetylcholinesterase activity.
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.
Kikuchi
Tatsuya
T
Department of Medical Imaging, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
Zhang
Ming-Rong
MR
Ikota
Nobuo
N
Fukushi
Kiyoshi
K
Okamura
Toshimitsu
T
Suzuki
Kazutoshi
K
Arano
Yasushi
Y
Irie
Toshiaki
T
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
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