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Structure-Activity Relationships of Radioiodinated 6,5,6-Tricyclic Compounds for the Development of Tau Imaging Probes.
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-01-09 , DOI: 10.1021/acsmedchemlett.9b00456
Hiroyuki Watanabe 1 , Haruka Tatsumi 1 , Sho Kaide 1 , Yoichi Shimizu 1 , Shimpei Iikuni 1 , Masahiro Ono 1
Affiliation  

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 in vitro autoradiography of AD brain sections, pyridoimidazopyridine and benzimidazopyrimidine derivatives ([125I]21 and [125I]22, respectively) showed selective binding affinity for tau aggregates, whereas carbazole, pyrrolodipyridine, and pyridoimidazopyrimidine derivatives ([125I]10, [125I]12, and [125I]23, respectively) bound β-amyloid aggregates. In a biodistribution study using normal mice, [125I]21 and [125I]22 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.

中文翻译:

放射性碘6,5,6-三环化合物的结构活性关系,用于开发Tau成像探针。

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氏病(AD)进展的有吸引力的成像靶标。在这项研究中,我们设计和合成了六个放射性碘化的6,5,6-三环化合物,以探索tau成像探针的新型支架。在AD脑切片的体外放射自显影中,吡啶并咪唑并吡啶衍生物和苯并咪唑并嘧啶衍生物(分别为[125I] 21和[125I] 22)显示出对tau聚集体的选择性结合亲和力,而咔唑,吡咯二吡啶和吡啶并咪唑并嘧啶衍生物([125I] 10,[125I ] 12和[125I] 23)分别结合了β-淀粉样聚集体。在使用正常小鼠进行的生物分布研究中,[125I] 21和[125I] 22显示出较高的初始摄取量(分别为5.73和5.66%ID / g,注射后2分钟)从大脑中快速冲洗(注射后60分钟分别为0.14和0.10%ID / g)。两者合计,包括吡啶并咪唑并吡啶和苯并咪唑并嘧啶的两种新型支架可以用于开发有用的tau成像探针。
更新日期:2020-01-10
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