Watanabe Hiroyuki, Tatsumi Haruka, Kaide Sho, Shimizu Yoichi, Iikuni Shimpei, Ono Masahiro
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
ACS Med Chem Lett. 2020 Jan 9;11(2):120-126. doi: 10.1021/acsmedchemlett.9b00456. eCollection 2020 Feb 13.
Tau aggregate, which is the main component of the neurofibrillary tangle, is an attractive imaging target for diagnosing and monitoring the progression of Alzheimer's disease (AD). In this study, we designed and synthesized six radioiodinated 6,5,6-tricyclic compounds to explore novel scaffolds for tau imaging probes. On autoradiography of AD brain sections, pyridoimidazopyridine and benzimidazopyrimidine derivatives ([I] and [I], respectively) showed selective binding affinity for tau aggregates, whereas carbazole, pyrrolodipyridine, and pyridoimidazopyrimidine derivatives ([I], [I], and [I], respectively) bound β-amyloid aggregates. In a biodistribution study using normal mice, [I] and [I] showed high initial uptakes (5.73 and 5.66% ID/g, respectively, at 2 min postinjection) into and rapid washout (0.14 and 0.10% ID/g, respectively, at 60 min postinjection) from the brain. Taken together, two novel scaffolds including pyridoimidazopyridine and benzimidazopyrimidine may be applied to develop useful tau imaging probes.
tau聚集体是神经原纤维缠结的主要成分，是诊断和监测阿尔茨海默病（AD）进展的一个有吸引力的成像靶点。在本研究中，我们设计并合成了六种放射性碘化的6,5,6-三环化合物，以探索用于tau成像探针的新型支架。在AD脑切片的放射自显影中，吡啶并咪唑并吡啶和苯并咪唑并嘧啶衍生物（分别为[I]和[I]）对tau聚集体表现出选择性结合亲和力，而咔唑、吡咯并二吡啶和吡啶并咪唑并嘧啶衍生物（分别为[I]、[I]和[I]）则与β-淀粉样蛋白聚集体结合。在使用正常小鼠的生物分布研究中，[I]和[I]在注射后2分钟时脑内的初始摄取率较高（分别为5.73%和5.66% ID/g），并在注射后60分钟时从脑内快速清除（分别为0.14%和0.10% ID/g）。综上所述，包括吡啶并咪唑并吡啶和苯并咪唑并嘧啶在内的两种新型支架可用于开发有用的tau成像探针。
