Matsumura Kenji, Ono Masahiro, Kitada Ayane, Watanabe Hiroyuki, Yoshimura Masashi, Iikuni Shimpei, Kimura Hiroyuki, Okamoto Yoko, Ihara Masafumi, Saji Hideo
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University , 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Pathology, National Cerebral and Cardiovascular Center , 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.
J Med Chem. 2015 Sep 24;58(18):7241-57. doi: 10.1021/acs.jmedchem.5b00440. Epub 2015 Sep 1.
In order to explore novel tau-imaging agents that can selectively detect neurofibrillary tangles in Alzheimer's disease (AD) brains, we designed and synthesized a series of heterocyclic phenylethenyl and (3-pyridinyl)ethenyl derivatives with or without a dimethyl amino group. In in vitro autoradiography using AD brain sections, all radioiodinated ligands with a dimethyl amino group bound to Aβ deposits in the sections. In contrast, the ligands without a dimethyl amino group showed different patterns of radioactivity accumulation in the sections depending on the kind of heterocycle contained in their molecules. Particularly, a phenylethenyl benzimidazole derivative ([(125)I]64) showed marked radioactivity accumulation in the temporal lobe which corresponded with the distribution of tau deposits. [(125)I]64 also showed the most favorable pharmacokinetics in normal mouse brains (3.69 and 0.06% ID/g at 2 and 60 min postinjection, respectively) among all ligands in this study. Taken together, these results suggest that [(123)I]64 may be a new candidate tau-imaging agent.
为了探索能够选择性检测阿尔茨海默病（AD）大脑中神经原纤维缠结的新型tau成像剂，我们设计并合成了一系列带有或不带有二甲氨基的杂环苯乙烯基和（3-吡啶基）乙烯基衍生物。在使用AD脑切片的体外放射自显影实验中，所有带有二甲氨基的放射性碘化配体都与切片中的Aβ沉积物结合。相比之下，不带有二甲氨基的配体在切片中显示出不同的放射性积累模式，这取决于其分子中所含杂环的种类。特别是，一种苯乙烯基苯并咪唑衍生物（[(125)I]64）在颞叶显示出明显的放射性积累，这与tau沉积物的分布相对应。在本研究的所有配体中，[(125)I]64在正常小鼠大脑中也显示出最有利的药代动力学（注射后2分钟和60分钟时分别为3.69和0.06% ID/g）。综上所述，这些结果表明[(123)I]64可能是一种新型的tau成像剂候选物。
