title: Novel benzofuran derivatives for PET imaging of beta-amyloid plaques in Alzheimer's disease brains.
abstract: A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.
authors.affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. mono@net.nagasaki-u.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ono
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kawashima
authors.forename: Akemi
authors.initials: A
authors.lastname: Nonaka
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kawai
authors.forename: Mamoru
authors.initials: M
authors.lastname: Haratake
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.forename: Mei-Ping
authors.initials: MP
authors.lastname: Kung
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.forename: Morio
authors.initials: M
authors.lastname: Nakayama
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D015394:Molecular Structure; D049268:Positron-Emission Tomography
chemical_list: D016229:Amyloid beta-Peptides; D001572:Benzofurans; C105430:benzofuran