Ono Masahiro, Haratake Mamoru, Saji Hideo, Nakayama Morio
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.
Bioorg Med Chem. 2008 Jul 15;16(14):6867-72. doi: 10.1016/j.bmc.2008.05.054. Epub 2008 May 29.
In the search for novel probes for the imaging in vivo of beta-amyloid plaques in Alzheimer's disease (AD) brain, we have synthesized and evaluated a series of 3,5-diphenyl-1,2,4-oxadiazole (DPOD) derivatives. The affinity for beta-amyloid plaques was assessed by an in vitro-binding assay using pre-formed synthetic Abeta42 aggregates. The new series of DPOD derivatives showed excellent affinity for Abeta aggregates with K(i) values ranging from 4 to 47nM. In biodistribution experiments using normal mice, [(125)I]12, [(125)I]13, [(125)I]14, and [(125)I]15 examined displayed sufficient uptake for imaging, ranging from 2.2 to 3.3% ID/g. But the washout of the four ligands from the brain was relatively slow. Although additional modifications are necessary to improve the uptake and rapid clearance of non-specifically bound radiotracers, the DPOD pharmacophore with high-binding affinity for Abeta aggregates may be useful as a backbone structure to develop novel beta-amyloid imaging agents.
在寻找用于阿尔茨海默病（AD）脑内β-淀粉样蛋白斑块体内成像的新型探针过程中，我们合成并评估了一系列3,5-二苯基-1,2,4-恶二唑（DPOD）衍生物。使用预先形成的合成β-淀粉样蛋白42聚集体通过体外结合试验评估对β-淀粉样蛋白斑块的亲和力。新系列的DPOD衍生物对β-淀粉样蛋白聚集体显示出优异的亲和力，其抑制常数（K(i)）值范围为4至47 nM。在使用正常小鼠的生物分布实验中，所检测的[125I]12、[125I]13、[125I]14和[125I]15显示出足以用于成像的摄取量，范围为2.2至3.3%注射剂量/克。但是这四种配体从脑中的洗脱相对较慢。尽管需要进行额外的修饰以改善非特异性结合放射性示踪剂的摄取和快速清除，但对β-淀粉样蛋白聚集体具有高结合亲和力的DPOD药效基团可能作为开发新型β-淀粉样蛋白成像剂的骨架结构是有用的。
