Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China.
J Med Chem. 2021 Oct 28;64(20):15420-15428. doi: 10.1021/acs.jmedchem.1c01477. Epub 2021 Oct 15.
We report the development of the first positron emission tomography (PET) radiotracer, [F]CNY-07, based on a highly specific and potent RIPK1 inhibitor, Nec-1s, for RIPK1/necroptosis brain imaging in rodents. [F]CNY-07 was synthesized through copper-mediated F-radiolabeling from an aryl boronic ester precursor and studied PET imaging in rodents. PET imaging results showed that [F]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 . Self-blocking studies of [F]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 [F]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.
我们报告了第一个正电子发射断层扫描（PET）示踪剂[F]CNY-07 的开发，该示踪剂基于一种高度特异性和有效的 RIPK1 抑制剂 Nec-1s，用于在啮齿动物中进行 RIPK1/坏死性凋亡的脑成像。[F]CNY-07 通过铜介导的芳基硼酸酯前体的 F-放射性标记合成，并在啮齿动物中进行了 PET 成像研究。PET 成像结果表明，[F]CNY-07 可以穿透血脑屏障，在注射后 10 分钟内，脑内每单位体积的最大注入剂量百分比为 3。在啮齿动物中用未标记的分子预先处理[F]CNY-07 的自我阻断研究表明，动物大脑中的放射性减少（放射性减少 30%），表明我们的示踪剂具有结合特异性。我们的研究表明，[F]CNY-07 提供了一种有用的 PET 放射性配体，可实现脑 RIPK1 成像，这可能是研究动物和潜在人类中与 RIPK1 相关的神经疾病的有价值的研究工具。
