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The Journal of Neuroscience, March 10, 2004, 24(10):2535-2541; doi:10.1523/JNEUROSCI.4456-03.2004

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Neurobiology of Disease
Styrylbenzoxazole Derivatives for In Vivo Imaging of Amyloid Plaques in the Brain

Nobuyuki Okamura,^1,4 Takahiro Suemoto,¹ Hiroshi Shimadzu,¹ Masako Suzuki,¹ Tsuyoshi Shiomitsu,¹ Hiroyasu Akatsu,² Takayuki Yamamoto,² Matthias Staufenbiel,³ Kazuhiko Yanai,⁴ Hiroyuki Arai,⁵ Hidetada Sasaki,⁵ Yukitsuka Kudo,¹ and Tohru Sawada¹

¹BF Research Institute, Suita 565-0873, Japan, ²Choju Medical Institute, Fukushimura Hospital, Toyohashi 441-8124, Japan, ³Nervous System Department, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland, and Departments of ⁴Pharmacology and ⁵Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai 980-8575, Japan

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- (A) 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 A1-42-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 specific in vivo labeling 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 (t_1/2 = 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.

Key words: amyloid- protein; Alzheimer's disease; senile plaques; neurofibrillary tangles; imaging; positron emission tomography

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Received Oct 1, 2003; revised December 16, 2003; accepted January 9, 2004.

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