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

点击翻译按钮获取中文摘要

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