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

Abstract

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-b (Ab) 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 Ab deposits were also evaluated using mice. For clinical evaluation of 11 C-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 11 C-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of 11 C-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 Ab1-42 fibrils (K i [inhibition constant], 4.3 6 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 11 C-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 Ab fibrils. Conclusion: These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.

Fluorinated Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains

“…[3][4][5] Recent success in developing radiolabeled agents targeting Aβ aggregates has provided a window of opportunity to improve the diagnosis of AD. Preliminary reports of PET imaging suggested that [ 9 showed differential uptake and retention in the brain of AD patients as compared to controls. However, 11 C is a positron-emitting isotope with a short t 1/2 (20 min), which limits its clinical application.…”

Neuroimaging in Dementia: In Vivo Amyloid Imaging

“…As levels of this Aβ subspecies in model mice are m u c h l o w e r t h a n t h o s e i n A D p a t i e n t s (Kawarabayashi et al 2001;Güntert et al 2006), these findings plausibly explain the advantages of high-SA tracers in the sensitive detection of mouse amyloid, and highlight the significance of Aβ -N3-pyroglutamate as a new diagnostic and therapeutic target. The established animal system has been applied to a comparison of multiple radiotracers, such as PIB and 11 C-BF-227 (Kudo et al 2007), in a collaborative work with Tohoku University, and was proven to facilitate the preclinical selection of PET imaging agents adequate for specific purposes, including early detection of amyloid formation, assessment of pathological progression and evaluation of therapeutic effects. Multitracer, multi-scan PET study is also of pivotal importance in the mechanistic evaluation of Aβ immunization and other related anti-amyloid treatments, as a PET ligand for peripheral benzodiazepine receptor, termed […”

Current and future uses of neuroimaging for cognitively impaired patients

“…Several small molecule probes for use with PET have been developed to provide measures of these deposits in vivo. [82][83][84][85][86] The most extensive experience has been with the amyloid-binding radiotracer [ 11 C]-labelled Pittsburgh compound B (2-[4L'-(methylamino)phenyl]-6-hydrobenzothiazole; PIB), a derivative of thioflavin-T amyloid dye that binds to amyloid-β plaques but not tangles. PET studies using [ 11 C]PIB show significantly greater cortical retention in patients with AD compared with controls ( figure 4).…”