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

Department of Pharmacology, Tohoku University, Miyagi, Japan
Journal of Nuclear Medicine (Impact Factor: 6.16). 04/2007; 48(4):553-61. DOI: 10.2967/jnumed.106.037556
Source: PubMed


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.
The binding affinity of BF-227 to amyloid-beta (Abeta) 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 Abeta 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.
BF-227 displayed high binding affinity to synthetic Abeta1-42 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 (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 Abeta fibrils.
These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.

Download full-text


Available from: Kazuhiko Yanai, Jan 28, 2014
  • Source
    • "nds selectively binding to ' classic ' components , as exemplified by DRM106 , would be of utility in assessing Ab pathologies intimately associated with neurotoxic insults . A few clinically available PET agents including 11 C - BF - 227 and 18 F - FACT , have been documented to bind to dense - cored , neuritic rather than non - classic plaques ( Kudo et al . 2007 ; Ito et al . 2014"
    [Show abstract] [Hide abstract]
    ABSTRACT: Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In the present study, we investigated the binding of several radioligands including (11) C-Pittsburgh Compound B ((11) C-PiB), (3) H-AZD2184, and two recently developed compounds, (125) I-DRM106 and (125) I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB. (11) C-PiB, (3) H-AZD2184 and (125) I-DRK092 showed overt binding to presubicular Aβ deposits, while (125) I-DRM106 barely bound to these aggregates, despite its strong binding in the hippocampal CA1 sector. Unlike neuritic plaques in the CA1, Aβ lesions in the presubiculum were not accompanied by inflammatory gliosis enriched with 18-kDa translocator protein (TSPO). Thus, there are at least two different components in Aβ aggregates providing distinct binding sites for the current amyloid radioligands, and one of these binding components is distinctly present in the presubicular Aβ deposits. Amyloid radioligands lacking affinity for this component, such as (125) I-DRM106, may selectively capture Aβ deposits tightly associated with TSPO-positive neuroinflammation and neurodegeneration as exemplified by CA1 neuritic plaques. Hence, comparative autoradiographic assessments of radioligand binding in CA1 and presubiculum could serve for the development of an amyloid PET imaging agent visualizing neurotoxicity-related Aβ pathologies. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Aug 2015 · Journal of Neurochemistry
  • Source
    • "In particular, radiolabelled *Address correspondence to this author at the CERMEP-Imaging Platform, 59 boulevard Pinel, Lyon, F-69003, France; Tel: (+33)472688609; Fax: (+33)472688610; E-mail: BF227 is a radioligand that was initially proposed for the diagnosis of Alzheimer disease thanks to its high affinity for amyloid plaques [8]. In 2009, an in vitro study reported the presence of high affinity binding sites towards -syn fibrils for [ 18 F]BF277 [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [18F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [18F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [18F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.
    Full-text · Article · Oct 2014 · Current Alzheimer research
    • "This revealed that in spite of using male age-matched animals in both groups, statistically significant and progressive variation in body weight was observed during the progression of the study (Fig. 1). With the aim of providing normalization for differences in the observed body weight, SUV, a well-established methodology for the assessment of a radiotracer uptake [21] [22] [23], was applied on each individual measure. Fig. 1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increased Glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders such as Alzheimer's disease, one of the earliest diseases linked to GSK-3 dysfunction. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this study we have characterised and evaluated the brain metabolic changes induced by GSK-3β overexpression in transgenic mice throughout their lifespan. The conditional Tet/GSK-3β transgenic line used in this study has been previously extensively characterized at the pathological, biochemical and cognitive levels. Now we have investigated the effect GSK-3β overexpression on the 18F-fluoro-deoxyglucose (FDG) uptake by positron emission tomography (PET), taking advantage from this non-invasive technique which has allowed us to track individually the same animals throughout their lives. The results obtained during the longitudinal analysis showed a reduction of metabolic activity in several brain regions, such as cortex, striatum and hippocampus, consistent with the areas where the transgene is being expressed. The reduction of the metabolic activity in these mice is observed from the first time point, performed at the age of 3 months, and maintained throughout the whole study, until the oldest age tested (19 months). This effect seems to be reverted in a satellite group of 3-month transgenic animals treated with the classical GSK-3 inhibitor lithium, as they show higher FDG uptake values compared with untreated age-matched transgenic animals.
    No preview · Article · Jul 2013
Show more