Synthesis and preliminary evaluation of 2-arylhydroxyquinoline derivatives for tau imaging
Synthesis and preliminary evaluation of 2-arylhydroxyquinoline derivatives for tau imaging
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DOI：
10.1002/jlcr.3133
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发表时间：
2014-01-01
影响因子：
1.8
通讯作者：
Kudo, Yukitsuka
中科院分区：
文献类型：
--
作者：
Tago, Tetsuro;Furumoto, Shozo;Kudo, Yukitsuka
阿尔茨海默病（AD）是痴呆症最常见的原因。老年斑，由β-淀粉样蛋白组成，和神经纤维缠结（NFT），由tau蛋白组成，是AD的代表性病理标志。据信，NFT的积累先于AD的临床症状的发作，并且与记忆功能障碍的进展相关。因此，使用非侵入性检测技术，包括放射性标记的探针和正电子发射断层扫描（PET）将有助于早期诊断或分期的AD。在这项研究中，我们合成和评估新的羟基化2-芳基喹啉衍生物作为tau成像PET探针。通过AD海马切片的荧光染色和使用[F-18]THK-523的竞争性结合测定来评估化合物对tau的结合亲和力。THK-951在AD脑切片和K18280 K原纤维中显示出对tau病理学的高结合亲和力（Ki =20.7nM）;因此，我们放射性合成了C-11标记的THK-951，并进一步研究了其作为tau PET探针的潜力。[C-11]THK-951在正常小鼠脑中表现出良好的动力学（注射后2分钟为3.23% ID/g，注射后30分钟为0.15% ID/g），并通过放射自显影试验显示AD脑切片中的NFT标记。这些发现表明[C-11]THK-951可用于AD中tau病理学的体内PET成像。版权所有（c）2013约翰威利父子有限公司
Alzheimer's disease (AD) is the most common cause of dementia. Senile plaques, consisting of -amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2-arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [F-18]THK-523. THK-951 showed high binding affinity for tau pathology in an AD brain section and K18280K fibrils (K-i=20.7nM); thus, we radiosynthesized a C-11-labeled THK-951 and further studied its potential as a tau PET probe. The [C-11]THK-951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2min postinjection and 0.15% ID/g at 30min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [C-11]THK-951 for in vivo PET imaging of tau pathology in AD. Copyright (c) 2013 John Wiley & Sons, Ltd.