Novel benzofuran derivatives for PET imaging of ƒÀ-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 Ki values in the subnanomolar range. Among these benzofuran derivatives,
compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest Ki 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 11C labeled compound 8, [11C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran,
with [11C]methyl triflate. The [11C]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, [11C]8, may be a useful candidate PET tracer for detecting amyloid plaques in
the brains of patients with Alzheimer's disease.