N-[18F]Fluoroethylpiperidin-4ylmethyl Acetate, a Novel Lipophilic Acetylcholine Analogue for PET Measurement of Brain Acetylcholinesterase Activity

• Published in: Journal of medicinal chemistry Vol. 48; no. 7; pp. 2577 - 2583
• Main Authors: Kikuchi, Tatsuya, Zhang, Ming-Rong, Ikota, Nobuo, Fukushi, Kiyoshi, Okamura, Toshimitsu, Suzuki, Kazutoshi, Arano, Yasushi, Irie, Toshiaki
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 07.04.2005; Amer Chemical Soc
• Subjects: Acetates - chemical synthesis; Acetates - chemistry; Acetates - pharmacokinetics; Acetylcholine - analogs & derivatives; Acetylcholine - chemical synthesis; Acetylcholine - chemistry; Acetylcholine - pharmacokinetics; Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Animals; Biological and medical sciences; Blood-Brain Barrier - metabolism; Brain - enzymology; Brain - metabolism; Chemistry, Medicinal; Cholinesterase Inhibitors - pharmacology; Contrast media. Radiopharmaceuticals; Fluorine Radioisotopes; Humans; Hydrolysis; In Vitro Techniques; Life Sciences & Biomedicine; Male; Medical sciences; Membranes, Artificial; Permeability; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacokinetics; Positron-Emission Tomography; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Tissue Distribution; POSITRON-EMISSION-TOMOGRAPHY; TRACER; RADIOTRACERS; ESTERS; Fluorine Isotopes; Fluorine 18; Radiolabelling; Rat; Enzyme; Rodentia; Central nervous system; Esterases; Acetylcholinesterase; Blood brain barrier; Biological activity; Carboxylic ester hydrolases; Lipophilic compound; Vertebrata; Mammalia; Absorption; Animal; Distribution; Hydrolases; Pharmacokinetics; Positron emission tomography
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049100w

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 11C-labeled acetylcholine analogues, N-[11C]methylpiperidin-4-yl acetate and propionate, and positron emission tomography (PET). Our aim was to develop an 18F-labeled acetylcholine analogue useful for brain AChE mapping with PET, since 18F, with a longer half-life, has advantages over 11C. In a preliminary study, a series of N-[14C]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 18F-labeled acetylcholine analogue, N-[18F]fluoroethylpiperidin-4-ylmethyl acetate. In rat experiments, the 18F-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.