Watanabe Hiroyuki, Kishimoto Takeaki, Kaide Sho, Tarumizu Yuta, Tatsumi Haruka, 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. 2021 Apr 26;12(5):805-811. doi: 10.1021/acsmedchemlett.1c00071. eCollection 2021 May 13.
The accumulation of hyperphosphorylated tau protein in the brain is regarded as one of the hallmarks of Alzheimer's disease (AD). In vivo imaging of tau aggregates is helpful for diagnosis and monitoring of the progression of AD. In this study, we designed and synthesized novel radioiodinated benzimidazopyrimidine (BIPM) and pyridoimidazopyridine (PIP) derivatives with a monomethylamino, monoethylamino, monopropylamino, or diethylamino group as tau imaging probes for single-photon-emission computed tomography (SPECT). On in vitro autoradiography with AD brain sections, [I]PIP-NHMe showed the highest selective binding affinity for tau aggregates among the radioiodinated BIPM and PIP derivatives. In a biodistribution study using normal mice, [I]PIP-NHMe and [I]PIP-NHEt displayed high initial uptake (6.62 and 6.86% ID/g, respectively, at 2 min postinjection) into and rapid clearance from the brain, with brain/brain ratios of 38.9 and 28.6, respectively. These results suggest that [I]PIP-NHMe may be a novel SPECT probe that is useful for detecting tau aggregates in the AD brain.
大脑中过度磷酸化tau蛋白的积累被视为阿尔茨海默病（AD）的标志性特征之一。tau聚集体的体内成像有助于AD的诊断和病情进展监测。在本研究中，我们设计并合成了带有单甲氨基、单乙氨基、单丙氨基或二乙氨基的新型放射性碘化苯并咪唑并嘧啶（BIPM）和吡啶并咪唑并吡啶（PIP）衍生物，作为用于单光子发射计算机断层扫描（SPECT）的tau成像探针。在对AD脑切片进行体外放射自显影时，[I]PIP-NHMe在放射性碘化的BIPM和PIP衍生物中对tau聚集体表现出最高的选择性结合亲和力。在使用正常小鼠的生物分布研究中，[I]PIP-NHMe和[I]PIP-NHEt在注射后2分钟时对大脑的初始摄取率较高（分别为6.62%和6.86% ID/g），并能迅速从大脑中清除，脑/脑比值分别为38.9和28.6。这些结果表明，[I]PIP-NHMe可能是一种新型的SPECT探针，可用于检测AD大脑中的tau聚集体。
