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2-(2-[2-Dimethylaminothiazol-5-yl]Ethenyl)-6- (2-[Fluoro]Ethoxy)Benzoxazole: A Novel PET Agent for In Vivo Detection of Dense Amyloid Plaques in Alzheimer's Disease Patients

¹ Tohoku University Biomedical Engineering Research Organization (TUBERO), Sendai, Japan; ² Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan; ³ Division of Cyclotron Nuclear Medicine, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan; ⁴ Department of Geriatrics and Gerontology, Center for Asian Traditional Medicine, Tohoku University School of Medicine, Sendai, Japan; and ⁵ Division of Radiopharmaceutical Chemistry, Cyclotron and Radioisotope Center, Tohoku University, Sendai, Japan

Correspondence: For correspondence or reprints contact: Nobuyuki Okamura, MD, Department of Pharmacology, Tohoku University School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: oka{at}mail.tains.tohoku.ac.jp

Extensive deposition of dense amyloid fibrils is a characteristic neuropathologic hallmark in Alzheimer's disease (AD). Noninvasive detection of these molecules is potentially useful for early and precise detection of patients with AD. This study reports a novel compound, 2-(2-[2-dimethylaminothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole (BF-227), for in vivo detection of dense amyloid deposits using PET. Methods: The binding affinity of BF-227 to amyloid-ß (Aß) fibrils was calculated. The binding property of BF-227 to amyloid plaques was evaluated by neuropathologic staining of AD brain sections. Brain uptake and in vivo binding of BF-227 to Aß deposits were also evaluated using mice. For clinical evaluation of ¹¹C-BF-227 as a PET probe, 11 normal (healthy) subjects and 10 patients with AD participated in this study. Dynamic PET images were obtained for 60 min after administration of ¹¹C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of ¹¹C-BF-227 retention. The regional tracer distribution in AD patients was statistically compared with that of aged normal subjects on a voxel-by-voxel basis. Results: BF-227 displayed high binding affinity to synthetic Aß1-42 fibrils (K_i [inhibition constant], 4.3 ± 1.5 nM). Neuropathologic staining has demonstrated preferential binding of this agent to dense amyloid deposits in AD brain. Moreover, a biodistribution study of this agent revealed excellent brain uptake and specific labeling of amyloid deposits in transgenic mice. The present clinical PET study using ¹¹C-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of normal subjects. All AD patients were clearly distinguishable from normal individuals using the temporal SUV ratio. Voxel-by-voxel analysis of PET images revealed that cortical BF-227 retention in AD patients is distributed primarily to the posterior association area of the brain and corresponded well with the preferred site for neuritic plaque depositions containing dense Aß fibrils. Conclusion: These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.

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