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In Vitro and In Vivo Evaluation of GSK-3 Radioligands in Alzheimer’s Disease: Preliminary Evidence of Sex Differences
ACS Pharmacology & Translational Science Pub Date : 2021-07-20 , DOI: 10.1021/acsptsci.1c00132
Ashley C Knight 1, 2 , Cassis Varlow 1, 2 , Junchao Tong 1 , Neil Vasdev 1, 2
Affiliation  

Glycogen synthase kinase-3 (GSK-3) is a positron emission tomography (PET) imaging target with implications in the pathogenesis of Alzheimer’s disease (AD). This preliminary study evaluates human AD and transgenic P301L mouse brain tissues using the GSK-3-targeting radiotracers [3H]PF-367 and [3H]OCM-44 in radioligand binding assays. A saturation analysis showed decreased GSK-3 density in female human AD compared to a normal healthy brain. Equivalence in density (Bmax), affinity (Kd), and apparent affinity (Ki) of both radiotracers was demonstrated to enable their interchangeability for in vitro evaluations of GSK-3 expression. An evaluation of P301L mouse brain by [3H]/[11C]OCM-44 delineated differences in the Bmax of GSK-3 between the control and transgenic mice within male subjects. PET imaging showed similar trends to those observed in vitro. Sex differences are revealed as a potential parameter to consider in the development of GSK-3-targeted diagnostics and therapeutics and could guide recruitment for clinical studies.

中文翻译:

阿尔茨海默病中 GSK-3 放射性配体的体外和体内评价:性别差异的初步证据

糖原合酶激酶 3 (GSK-3) 是一种正电子发射断层扫描 (PET) 成像靶标,与阿尔茨海默病 (AD) 的发病机制有关。这项初步研究在放射性配体结合测定中使用 GSK-3 靶向放射性示踪剂 [ 3 H]PF-367 和 [ 3 H]OCM-44 评估人类 AD 和转基因 P301L 小鼠脑组织。饱和度分析显示,与正常健康大脑相比,女性人类 AD 中的 GSK-3 密度降低。两种放射性示踪剂在密度 ( B max )、亲和力 ( K d ) 和表观亲和力 ( K i ) 方面的等效性被证明能够使它们在体外评估 GSK-3 表达时具有互换性。P301L 小鼠大脑的评估 [3 H]/[ 11 C]OCM-44 描绘了雄性受试者中对照和转基因小鼠之间 GSK-3的B max差异。PET 成像显示出与体外观察到的相似趋势。性别差异被认为是开发 GSK-3 靶向诊断和治疗的潜在参数,可以指导临床研究的招募。
更新日期:2021-08-13
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