title: Is subnanomolar binding affinity required for the in vivo imaging of acetylcholinesterase? Studies on 18F-labeled G379.
abstract: Acetylcholinesterase (AChE) is an important cholinergic marker of Alzheimer's disease (AD) and shows reduced activity in postmortem AD brain tissues. 1-(4-Fluorobenzyl)-4-[(5,6-dimethoxy-1-oxoindan-2-fluoro-2-yl)methyl]piperidine (G379, ), an AChE inhibitor with a subnanomolar IC(50) (0.56 nM), was prepared as a (18)F-labeled radioligand ([(18)F]) and evaluated in mice. Metabolism studies of [(18)F] showed no metabolites in the mouse brain. Tissue distribution studies demonstrated its uniform regional distribution in the mouse brain, suggesting that this radioligand is not suitable for the in vivo imaging of AChE. This result along with reports on radiolabeled N-benzylpiperidine lactam benzisoxazole (IC(50) < 1 nM) and other radiolabeled benzylpiperidine derivatives (IC(50) > 1 nM) suggested that a subnanomolar IC(50) may not be the only important factor in determining the suitability of a radioligand for in vivo studies of AChE.
authors.affiliation: Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Sang-Yoon
authors.initials: SY
authors.lastname: Lee
authors.forename: Yearn Seong
authors.initials: YS
authors.lastname: Choe
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Iimura
authors.forename: Yong
authors.initials: Y
authors.lastname: Choi
authors.forename: Kyung-Han
authors.initials: KH
authors.lastname: Lee
authors.forename: Byung-Tae
authors.initials: BT
authors.lastname: Kim
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D007189:Indans / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D008832:Microchemistry / Q000379:methods; D036103:Nanotechnology / Q000379:methods; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D011485:Protein Binding; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: C510969:1-(4-fluorobenzyl)-4-((5,6-dimethoxy-1-oxoindan-2-fluoro-2-yl)methyl)piperidine; D005462:Fluorine Radioisotopes; D007189:Indans; D010880:Piperidines; D019275:Radiopharmaceuticals; D000110:Acetylcholinesterase