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.