In Vivo Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains.

阿尔茨海默病大脑中 β-淀粉样斑块的体内成像。

基本信息

批准号：
15390014
负责人：
NAKAYAMA Morio
金额：
$ 7.49万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Formation and accumulation of β-amyloid (Aβ) peptide aggregates in the brain are critical factors in the development and progression of Alzheimer's disease (AD). In vivo imaging of amyloid plaques may lead to early detection of AD and monitoring the progression and effectiveness of AD treatment. In vivo imaging probes, showing high binding affinity for Aβ aggregates, and high brain penetrations, are essential for imaging of amyloid plaques in Alzheimer's disease. Recently, many agents based on Congo red and thioflavin have been reported as potential imaging agents. We have synthesized and evaluated benzofuran and stilbene derivatives labeled with ^<123>I and ^<11>C as PET and SPECT probes for imaging amyloid plaques in Alzheimer's disease. The results has prompted us to further search for effective and more practical amyloid imaging probe having a noble core structure.It has been previously shown that some flavones may have binding affinity to amyloid plaques in research into the mecha … More nism behind the anti-amyloidogenic activity of flavones. In this study, a series of flavone derivatives was designed and synthesized. Preparation of radioiodinated flavone was carried out by an iododestannylation reaction catalyzed by hydrogen peroxide. The log PC value of these flavones varied from 1.9 to 2.7, spanning the optimum range. The binding affinities for amyloid plaques were assessed by in vitro binding assay using pre-formed synthetic Aβ aggregates. The binding affinities of some compounds for Aβ (1-40) and Aβ (1-42) aggregates varied from 13nM to 77nM. When in vitro plaque labeling was carried out using post-mortem AD brain sections, all flavones intensely stained not only, amyloid plaques, but also cerebrovascular amyloids. The in vivo pharmacokinetic properties of radioiodinated flavone derivatives were evaluated in normal mice with standard biodistribution studies. Several compounds displayed high brain uptakes ranging from 3.2 to 4.1%ID/g at 2min post injection. The radioactivity was washed out from the brain rapidly (0.5-1.9%ID/g at 30min), which is highly desirable for amyloid imaging agents. These results suggest that the classes of radioiodinated flavones may be useful candidates as potential imaging agents for amyloid plaques. Less

大脑中 β-淀粉样蛋白 (Aβ) 肽聚集体的形成和积累是阿尔茨海默病 (AD) 发生和进展的关键因素，淀粉样斑块的体内成像可能有助于早期检测 AD 并监测其进展和有效性。 AD 治疗体内成像探针对 Aβ 聚集物表现出高结合亲和力和高脑渗透性，对于阿尔茨海默氏病淀粉样斑块的成像至关重要。最近，许多基于刚果红和硫黄素的试剂。已被报道为潜在的显像剂。我们已经合成并评估了用^ 123 I和^ 11 C标记的苯并呋喃和茋衍生物作为用于阿尔茨海默病中淀粉样蛋白斑成像的PET和SPECT探针。寻找有效且更实用的具有高贵核心结构的淀粉样蛋白成像探针。之前在机甲研究中已经表明，一些黄酮可能与淀粉样蛋白斑块具有结合亲和力……黄酮抗淀粉样蛋白形成活性背后的更多信息在本研究中，通过过氧化氢催化的碘脱二烷基化反应制备了一系列黄酮衍生物。这些黄酮的 log PC 值各不相同。 1.9 至 2.7，跨越最佳范围通过使用预形成的体外结合测定来评估淀粉样斑块的结合亲和力。一些化合物对 Aβ (1-40) 和 Aβ (1-42) 聚集体的结合亲和力从 13nM 到 77nM 不等。不仅对淀粉样斑块进行染色，还对脑血管淀粉样蛋白进行了染色。在正常小鼠中评估了放射性碘黄酮衍生物的体内药代动力学特性。通过标准的生物分布研究，几种化合物在注射后 2 分钟显示出 3.2%ID/g 至 4.1%ID/g 的高脑摄取量，放射性物质迅速从大脑中被清除（30 分钟时为 0.5-1.9%ID/g），这是非常理想的。这些结果表明，放射性碘黄酮类可能是淀粉样斑块的潜在显像剂。