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The Journal of Neuroscience, November 23, 2005, 25(47):10857-10862; doi:10.1523/JNEUROSCI.1738-05.2005

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BRIEF COMMUNICATION
Quinoline and Benzimidazole Derivatives: Candidate Probes for In Vivo Imaging of Tau Pathology in Alzheimer's Disease

Nobuyuki Okamura,^1,2 Takahiro Suemoto,¹ Shozo Furumoto,³ Masako Suzuki,¹ Hiroshi Shimadzu,¹ Hiroyasu Akatsu,⁴ Takayuki Yamamoto,⁴ Hironori Fujiwara,⁵ Miyako Nemoto,⁶ Masahiro Maruyama,⁶ Hiroyuki Arai,⁵ Kazuhiko Yanai,² Tohru Sawada,¹ and Yukitsuka Kudo^1,3

¹BF Research Institute, Osaka 541-0045, Japan, ²Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan, ³Tohoku University Biomedical Engineering Research Organization, Sendai 980-8575, Japan, ⁴Choju Medical Institute, Fukushimura Hospital, Toyohashi 441-8124, Japan, and Departments of ⁵Geriatric and Complementary Medicine and ⁶Geriatric and Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan

Neurofibrillary tangles (NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimer's disease (AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine (BF-126), 2-[(4-methylamino)phenyl]quinoline (BF-158), and 2-(4-aminophenyl)quinoline (BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to -amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using ¹¹C-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.

Key words: imaging; neuropathology; A peptide; tau; neurofibrillary tangles; paired helical filaments

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Received May 2, 2005; revised September 26, 2005; accepted September 27, 2005.

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