Abstract：
Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer\'s disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially other RIPK1-related human studies.
摘要：
靶向受体相互作用蛋白激酶1（RIPK1）已成为神经退行性疾病的有希望的治疗策略，特别是阿尔茨海默病（AD）。能够进行脑RIPK1成像的正电子发射断层扫描（PET）探针可以提供强大的工具来揭示与RIPK1相关的神经病理学。在这里，一种新的PET放射性配体的开发，[11C]据报道，CNY-10这可能使大脑RIPK1成像。[11C]CNY-10是以高放射化学产率(41.8%)和摩尔活性(305GBq/μmol)放射合成的。[11C]CNY-10的特征是在啮齿动物和非人灵长类动物中进行PET成像，表现出良好的大脑穿透力，结合特异性，和合适的清除动力学曲线。[11C]CNY-10在人类AD和健康对照死后脑组织中进行放射自显影，这表明AD大脑中的强放射信号高于健康对照。随后，使用基于[11C]CNY-10的PET研究结合免疫组织化学利用5xFAD小鼠模型对AD中的RIPK1进行进一步表征。发现AD小鼠显示的RIPK1脑信号明显高于WT对照小鼠，并且RIPK1与大脑中的淀粉样蛋白斑块密切相关。这些研究使[11C]CNY-10对AD的进一步翻译研究以及潜在的其他与RIPK1相关的人类研究成为可能。
