Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines As Imaging Agents for Tau Fibrils and β-Amyloid Plaques in Alzheimer's Disease Models
Bis(arylvinyl)pyrazines, -pyrimidines, and -pyridazines As Imaging Agents for Tau Fibrils and β-Amyloid Plaques in Alzheimer's Disease Models
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DOI：
10.1021/jm300653b
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发表时间：
2012-11-08
影响因子：
7.3
通讯作者：
Schmidtt, Boris
中科院分区：
文献类型：
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作者：
Bolaender, Alexander;Kieser, Daniel;Schmidtt, Boris
阿尔茨海默病（AD）的体内诊断具有很高的社会经济意义，并且仍然是一个要求很高的研究领域。该疾病的生物病理学特征是由聚集的β-淀粉样肽（A β）和tau蛋白衍生的细胞内缠结组成的细胞外斑块。在这里，我们报告的合成和评价荧光吡嗪，嘧啶和哒嗪衍生物在体外和体内的目的是在tau为基础的诊断AD。通过荧光显微镜对人脑组织进行了预评估，发现探针以高对比度和特异性标记了所有已知的疾病相关改变。为了定量结合亲和力，开发了一种新的噻嗪红置换试验，并对选定的候选物进行了毒理学分析。在转基因小鼠模型中的应用证明了一种化合物的生物利用度和脑渗透性。在组织学测试的过程中，我们发现了AD相关的tau聚集体在嗅上皮的鲍曼氏腺中的沉积，这具有在嗅觉系统中内镜诊断AD的潜力。
The in vivo diagnosis of Alzheimer's disease (AD) is of high socioeconomic interest and remains a demanding field of research. The biopathological hallmarks of the disease are extracellular plaques consisting of aggregated beta-amyloid peptides (A beta) and tau protein derived intracellular tangles. Here we report the synthesis and evaluation of fluorescent pyrazine, pyrimidine,and pyridazine derivatives in vitro and in vivo aiming at a tau-based diagnosis of AD. The probes were pre-evaluated on human brain tissue by fluorescence microscopy and were found to label all known disease-related alterations at high contrast and specificity. To quantify the binding affinity, a new thiazine red displacement assay was developed and selected candidates were toxicologically profiled. The application in transgenic mouse models demonstrated bioavailability and brain permeability for one compound. In the course of histological testing, we discovered an AD-related deposition of tau aggregates in the Bowman's glands of the olfactory epithelium, which holds potential for an endoscopic diagnosis of AD in the olfactory system.