Novel benzofuran derivatives for PET imaging of beta-amyloid plaques in Alzheimer's disease brains.
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.
Ono
Masahiro
M
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
Kawashima
Hidekazu
H
Nonaka
Akemi
A
Kawai
Tomoki
T
Haratake
Mamoru
M
Mori
Hiroshi
H
Kung
Mei-Ping
MP
Kung
Hank F
HF
Saji
Hideo
H
Nakayama
Morio
M
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
D016229:Amyloid beta-Peptides; D001572:Benzofurans; C105430:benzofuran