Structure-Activity Relationships of Radioiodinated Benzoimidazopyridine Derivatives for Detection of Tau Pathology
Structure-Activity Relationships of Radioiodinated Benzoimidazopyridine Derivatives for Detection of Tau Pathology
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DOI：
10.1021/acsmedchemlett.8b00092
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发表时间：
2018-05-01
影响因子：
4.2
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
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作者：
Kaide, Sho;Ono, Masahiro;Saji, Hideo
一般认为，由tau蛋白组成的神经元缠结参与阿尔茨海默病（AD）的发病机制。为了选择性检测tau病理学，我们合成并评估了具有烷基氨基的放射性碘化苯并咪唑并吡啶（BIP）衍生物作为tau成像探针。BIP衍生物对tau聚集体的体外选择性和体内药代动力学变化显著，强烈依赖于烷基氨基。在AD脑切片的体外放射自显影中，具有二甲氨基的BIP衍生物（BIP-NMe 2）显示出对tau聚集体的最高选择性。关于使用正常小鼠的生物分布，具有乙氨基的BIP衍生物（BIP-NHEt）显示出最高的脑摄取（注射后2分钟为6.04% ID/g）和快速的脑洗脱（注射后60分钟为0.12% ID/g）。这些结果表明，在BIP支架中引入最佳的烷基氨基可能会导致开发更有潜力的tau成像探针。
It is generally accepted that neurofibrillary tangles consisting of tau proteins are involved in the pathogenesis of Alzheimer's disease (AD). For selective detection of tau pathology, we synthesized and evaluated radioiodinated benzoimidazopyridine (BIP) derivatives with an alkylamino group as tau imaging probes. In vitro selectivity to tau aggregates and in vivo pharmacokinetics of BIP derivatives varied markedly, being strongly dependent on the alkylamino group. In in vitro autoradiography with AD brain sections, the BIP derivative with a dimethylamino group (BIP-NMe2) showed the highest selectivity to tau aggregates. Regarding the biodistribution using normal mice, the BIP derivative with an ethylamino group (BIP-NHEt) showed the highest uptake (6.04% ID/g at 2 min postinjection) into and rapid washout (0.12% ID/g at 60 min postinjection) from the brain. These results suggest that the introduction of an optimal alkylamino group into the BIP scaffold may lead to the development of more potential tau imaging probes.