Visualization of Receptor-Interacting Protein Kinase 1 (RIPK1) by Brain Imaging with Positron Emission Tomography

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.本研究报道了首款基于高特异性强效受体相互作用蛋白激酶1（Receptor-interacting protein kinase 1，RIPK1）抑制剂Nec-1s的正电子发射断层显像（positron emission tomography，PET）放射性示踪剂[¹⁸F]CNY-07的开发过程，用于啮齿类动物体内RIPK1/细胞坏死性凋亡（necroptosis）脑成像。[¹⁸F]CNY-07通过芳基硼酸酯前体经铜介导的¹⁸F放射性标记合成，并在啮齿类动物中开展了体内PET成像研究。PET成像结果显示，[¹⁸F]CNY-07可穿透血脑屏障，在活体脑内注射后10分钟时，每单位体积的最大注射剂量百分比可达3。通过对啮齿类动物预先给予未标记分子开展的[¹⁸F]CNY-07自阻断实验显示，动物脑内的放射性活度降低了30%，表明该放射性示踪剂具有结合特异性。本研究证实，[¹⁸F]CNY-07可作为一种实用的PET放射性配体，实现脑内RIPK1成像，有望成为研究动物及潜在人类体内RIPK1相关神经系统疾病的宝贵研究工具。