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
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
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DOI：
10.2967/jnumed.106.037556
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发表时间：
2007-04-01
影响因子：
9.3
通讯作者：
Arai, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kudo, Yukitsuka;Okamura, Nobuyuki;Arai, Hiroyuki
广泛沉积致密的淀粉样蛋白纤维是阿尔茨海默病(AD)的典型神经病理特征。对这些分子的非侵入性检测可能有助于AD患者的早期和准确检测。这项研究报告了一种新的化合物，2-(2-[2-dimethylamininothiazol-5-yl]ethenyl)-6-(2-[fluoro]ethoxy)benzoxazole(BF-227)，用于利用正电子发射计算机断层扫描技术在体内检测致密的淀粉样沉积。方法：计算BF-227与淀粉样β蛋白(Aβ)纤维的结合亲和力。通过AD脑切片神经病理染色评价BF-227与淀粉样斑块的结合特性。脑部摄取和体内BF-227与Aβ沉淀物的结合也用小鼠进行了评估。为了评价C-11-BF-227作为PET探针的临床应用价值，11名正常人和10名AD患者参与了这项研究。注射C-11-BF-227 60min后进行PET动态成像。计算局部标准化摄取值(SUV)和局部与小脑SUV的比值作为C-11-BF-227滞留的指标。AD患者的区域示踪剂分布在逐个体素的基础上与老年正常人的区域示踪剂分布进行统计比较。结果：BF-227与人工合成的Aβ1-42纤维具有较高的亲和力(K-I[抑制常数]，4.3+/-1.5 nm)。神经病理染色显示该制剂优先与AD脑中致密的淀粉样沉积结合。此外，这种制剂的生物分布研究显示，转基因小鼠具有良好的大脑摄取和淀粉样蛋白沉积的特异性标记。目前使用C-11-BF-227的临床PET研究表明，该示踪剂在AD患者的大脑皮层中保留，而在正常人的大脑皮层中不保留。使用颞叶SUV比率可以清楚地将所有AD患者与正常人区分开来。对PET图像的逐个体素分析显示，AD患者的皮质BF-227滞留主要分布在大脑的后关联区，并与含有致密Aβ纤维的神经炎斑块沉积的首选部位很好地对应。结论：BF-227是一种在AD患者体内检测致密淀粉样蛋白沉积的有前景的PET探针。
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-dimethylamininothiazol-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-beta (A beta) 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 A beta deposits were also evaluated using mice. for clinical evaluation of C-11-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 C-11-BF-227. The regional standardized uptake value (SUV) and the ratio of regional to cerebellar SUV were calculated as an index of C-11-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 A beta 1-42 fibrils (K-i [inhibition constant], 4.3 +/- 1.5nM). 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 C-11-BF-227 demonstrated the retention of this tracer in cerebral cortices of AD patients but not in those of 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 A beta fibrils. Conclusion: These findings suggest that BF-227 is a promising PET probe for in vivo detection of dense amyloid deposits in AD patients.