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Visualization of Receptor-Interacting Protein Kinase 1 (RIPK1) by Brain Imaging with Positron Emission Tomography
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-15 , DOI: 10.1021/acs.jmedchem.1c01477
Yu Lan 1, 2 , Ping Bai 1 , Yan Liu 1 , Sepideh Afshar 3 , Robin Striar 1 , Anna Kathryn Rattray 1 , Tyler Nicholas Meyer 1 , Amelia G Langan 1 , Alisa M Posner 1 , Shiqian Shen 4 , Rudolph E Tanzi 5 , Can Zhang 5 , Changning Wang 1
Affiliation  

We report the development of the first positron emission tomography (PET) radiotracer, [18F]CNY-07, based on a highly specific and potent RIPK1 inhibitor, Nec-1s, for RIPK1/necroptosis brain imaging in rodents. [18F]CNY-07 was synthesized through copper-mediated 18F-radiolabeling from an aryl boronic ester precursor and studied in vivo PET imaging in rodents. PET imaging results showed that [18F]CNY-07 can penetrate the blood–brain barrier with a maximum percent injected dose per unit volume of 3 at 10 min postinjection in the brain in vivo. Self-blocking studies of [18F]CNY-07 by pretreating with unlabeled molecules in rodents showed reduced radioactivity in animal brains (30% radioactivity decreased), indicating the binding specificity of our radiotracer. Our studies demonstrate that [18F]CNY-07 has provided a useful PET radioligand enabling brain RIPK1 imaging, which could be a valuable research tool in studying RIPK1-related neurological disorders in animals and potentially humans.

中文翻译:

通过正电子发射断层扫描的脑成像可视化受体相互作用蛋白激酶 1 (RIPK1)

我们报告了第一个正电子发射断层扫描 (PET) 放射性示踪剂 [ 18 F]CNY-07 的开发,它基于一种高度特异性和有效的 RIPK1 抑制剂 Nec-1s,用于啮齿动物的 RIPK1/坏死性脑死亡成像。[ 18 F]CNY-07 是通过铜介导的18 F-放射性标记从芳基硼酸酯前体合成的,并在啮齿动物体内研究了PET 成像。PET 成像结果表明,[ 18 F]CNY-07在体内脑内注射后 10 分钟可穿透血脑屏障,每单位体积的最大注射剂量百分比为 3 。[ 18 ]的自阻塞研究F]CNY-07 通过在啮齿动物中用未标记分子进行预处理显示动物大脑中的放射性降低(放射性降低 30%),表明我们的放射性示踪剂具有结合特异性。我们的研究表明,[ 18 F]CNY-07 提供了一种有用的 PET 放射性配体,可实现大脑 RIPK1 成像,这可能是研究动物和潜在人类中 RIPK1 相关神经系统疾病的有价值的研究工具。
更新日期:2021-10-28
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