Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
Eur J Med Chem. 2015 Nov 2;104:86-96. doi: 10.1016/j.ejmech.2015.09.028. Epub 2015 Sep 26.
A new series of fluoro-pegylated benzyloxybenzenes were designed, synthesized and evaluated as PET probes for early detection of Aβ plaques. Molecular docking revealed that all of the flexible benzyloxybenzenes inserted themselves into the hydrophobic Val18_Phe20 cleft on the flat spine of the Aβ fiber, in a manner similar to that of IMPY molecule. The most potent probe, [(18)F]9a, exhibited a combination of high binding affinity to Aβ aggregates (Ki = 21.0 ± 4.9 nM), high initial brain uptake (9.14% ID/g at 2 min), fast clearance from normal brain tissue (1.79% ID/g at 60 min), and satisfactory in vivo biostability in the brain (95% of intact form at 2 min). [(18)F]9a clearly labeled Aβ plaques in in vitro autoradiography of postmortem AD patients and Tg mice brain sections. Ex vivo autoradiography further demonstrated that [(18)F]9a did penetrate the intact BBB and specifically bind to Aβ plaques in vivo. Overall, [(18)F]9a may be a potential PET probe for imaging Aβ plaques in AD brains.
设计、合成并评价了一系列新的氟代聚乙二醇化苯氧基苯作为用于早期检测 Aβ 斑块的 PET 探针。分子对接显示，所有柔性苯氧基苯都以类似于 IMPY 分子的方式插入 Aβ 纤维平坦突上的疏水 Val18_Phe20 裂缝中。最有效的探针 [(18)F]9a 表现出与 Aβ 聚集物高结合亲和力（Ki = 21.0 ± 4.9 nM）、高初始脑摄取（2 分钟时 9.14% ID/g）、从正常脑组织快速清除（60 分钟时 1.79% ID/g）和良好的脑内体内稳定性（2 分钟时 95%为完整形式）的结合。[(18)F]9a 清楚地标记了 AD 患者死后和 Tg 小鼠脑切片的体外放射自显影中的 Aβ 斑块。离体放射自显影进一步表明，[(18)F]9a 确实穿透了完整的 BBB，并在体内特异性结合 Aβ 斑块。总体而言，[(18)F]9a 可能是一种用于 AD 大脑中 Aβ 斑块成像的潜在 PET 探针。
