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）胡椒骨料的形成和积累是阿尔茨海默氏病（AD）发展和发展的关键因素。淀粉样蛋白斑块的体内成像可能会导致AD的早期检测并监测AD治疗的进展和有效性。体内成像问题，表现出对Aβ聚集体的高结合亲和力以及脑渗透高的亲和力，对于阿尔茨海默氏病淀粉样蛋白斑块的成像至关重要。最近，许多基于刚果红和硫牛素的药物被报道为潜在的成像剂。我们已经合成并评估了标记为 ^<123> i和 ^<11> c的苯并富龙和硅衍生物为PET，以及在阿尔茨海默氏病中成像淀粉样蛋白斑块的SPECT问题。结果促使我们进一步寻找具有崇高核心结构的有效且更实用的淀粉样蛋白成像探针。以前已经证明，某些黄酮在对机甲的研究中可能具有与淀粉样蛋白斑的结合亲和力……在抗淀粉样蛋白的抗淀粉样生殖活性背后的更多NISM。在这项研究中，设计和合成了一系列黄酮衍生物。放射性置的黄酮的制备是通过通过过氧化氢催化的碘植氨酸反应进行的。这些黄酮的日志PC值从1.9到2.7不等，涵盖了最佳范围。通过使用预形成的合成Aβ聚集体进行体外结合测定法评估了淀粉样蛋白斑块的结合亲和力。 Aβ（1-40）和Aβ（1-42）聚集体的某些化合物的结合亲和力从13nm到77nm不等。当使用验尸后的脑部切片进行体外斑块标记时，所有黄酮不仅染色，不仅染色，而且淀粉样蛋白斑块，而且染色。通过标准的生物分布研究，在正常小鼠中评估了放射性结合黄酮衍生物的体内药代动力学特性。注射后2分钟时，几种化合物显示出高脑摄取范围为3.2至4.1％/g。放射性迅速从大脑中冲出（30分钟时ID/G 0.5-1.9％），这对于淀粉样蛋白成像剂非常可取。这些结果表明，放射性约束的黄酮类可能是有用的候选物，作为淀粉样蛋白斑块的潜在成像剂。较少的