Quinoline and benzimidazole derivatives:: Candidate probes for in vivo imaging of tau pathology in Alzheimer's disease
Quinoline and benzimidazole derivatives:: Candidate probes for in vivo imaging of tau pathology in Alzheimer's disease
复制标题
DOI：
10.1523/jneurosci.1738-05.2005
复制
发表时间：
2005-11-23
影响因子：
5.3
通讯作者：
Kudo, Y
中科院分区：
文献类型：
--
作者：
Okamura, N;Suemoto, T;Kudo, Y
神经纤维缠结（NFT）、神经纤维丝和老年斑的神经炎成分主要包含过度磷酸化的tau蛋白，并且代表阿尔茨海默病（AD）的病理特征。这些病变发生在临床症状出现之前，并与痴呆的严重程度相关。因此，这些病变的体内检测将证明可用于AD的临床前诊断和跟踪疾病进展。本研究介绍了三种新型化合物，4-[2-（2-苯并咪唑基）乙烯基]-N，N-二乙基苯胺（BF-126），2-[（4-甲氨基）苯基]喹啉（BF-158），和2-（4-氨基苯基）喹啉（BF-170），作为候选探针在体内成像的tau病理在AD脑。当将这些化合物的溶液静脉注射到正常小鼠中时，这些药剂表现出优异的脑摄取和从正常脑组织中的快速清除。与先前报道的探针BF-168相比，这些化合物显示出相对较低的对β-淀粉样蛋白原纤维的结合亲和力和较高的对tau原纤维的结合亲和力。在使用AD脑切片的神经病理学检查中，BF-126、BF-158和BF-170清楚地可视化NFT、神经纤维丝和成对螺旋状顺时针型神经炎。使用C-11标记的BF-158的放射自显影进一步证明了AD脑切片中NFT的标记。这些发现表明喹啉和苯并咪唑衍生物用于AD中tau病理学的体内成像的潜在有用性。
Neurofibrillary tangles ( NFTs), neuropil threads, and neuritic elements of senile plaques predominantly comprise hyperphosphorylated tau protein and represent pathological characteristics of Alzheimer's disease ( AD). These lesions occur before the presentation of clinical symptoms and correlate with the severity of dementia. In vivo detection of these lesions would thus prove useful for preclinical diagnosis of AD and for tracking disease progression. The present study introduces three novel compounds, 4-[2-(2-benzoimidazolyl)ethenyl]-N,N-diethylbenzenamine ( BF-126), 2-[( 4- methylamino) phenyl] quinoline ( BF-158), and 2-( 4- aminophenyl) quinoline ( BF-170), as candidate probes for in vivo imaging of tau pathology in the AD brain. When solutions of these compounds are injected intravenously into normal mice, these agents exhibit excellent brain uptake and rapid clearance from normal brain tissue. These compounds display relatively lower binding affinity to beta-amyloid fibrils and higher binding affinity to tau fibrils, compared with previously reported probe BF-168. In neuropathological examination using AD brain sections, BF-126, BF-158, and BF-170 clearly visualize NFTs, neuropil threads, and paired helical filament-type neuritis. Autoradiography using C-11-labeled BF-158 further demonstrated labeling of NFTs in AD brain sections. These findings suggest the potential usefulness of quinoline and benzimidazole derivatives for in vivo imaging of tau pathology in AD.