Styrylbenzoxazole Derivatives forIn VivoImaging of Amyloid Plaques in the Brain

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Abstract
Progressive deposition of senile plaques (SPs) is one of the major neuropathological features of Alzheimer's disease (AD) that precedes cognitive decline. Noninvasive detection of SPs could, therefore, be a potential diagnostic test for early detection of AD patients. For imaging SPs in the living brain, we have developed a series of styrylbenzoxazole derivatives that achieve high binding affinity for amyloid-β (Aβ) fibrils. One of these compounds, 6-(2-Fluoroethoxy)-2-[2-(4-methylaminophenil) ethenyl]benzoxazole (BF-168), selectively binds SPs in AD brain sections and recognizes Aβ1-42-positive diffuse plaques as well as neuritic plaques in AD brain sections. Intravenous injection of BF-168 in PS1/APP and APP23 transgenic mice resulted in specificin vivolabeling to both compact and diffuse amyloid deposits in the brain. In addition,18F-radiolabeled BF-168 demonstrated abundant initial brain uptake (3.9% injected dose/gm at 2 min after injection) and fast clearance (t1/2= 24.7 min) after intravenous administration in normal mice. Furthermore, autoradiograms of brain sections from APP23 transgenic mice at 180 min after intravenous injection of [18F]BF-168 showed selective labeling of brain amyloid deposits with little nonspecific binding. These findings strongly suggest that styrylbenzoxazole derivatives are promising candidate probes for positron emission tomography and single-photon emission computed tomography imaging for early detection of amyloid plaque formation.