基于空间构型与生物学特性以PSMA为靶点的68Ga/177Lu诊疗一体化核药研究

68Ga/177Lu-前列腺特异性膜抗原(PSMA)是近年来用于转移性去势抵抗前列腺癌备受关注的诊疗一体化药物，但存在肿瘤摄取与内化不足、且68Ga/177Lu完全依赖进口等关键问题。项目组开展了68Ga/177Lu前期研发，并发现PSMA小分子抑制剂空间结构对前列腺癌亲和性和内化率有重要影响。本研究以硫脲二肽等为骨架结构，修饰赖氨酸支链氨基，用模拟肽提升药物内化率，合成系列硫脲二肽等小肽衍生物；研发国产68Ga/177Lu，并进行标记，构建新型靶向PSMA诊疗一体化核药。体外实验检测标记物亲和性、内化率和安全性，通过micro-PET/CT及SPECT/CT等显像技术，深入探索68Ga/177Lu-PSMA体内生物分布与代谢、靶向诊断和治疗等构效关系。具有自主知识产权的新型核药68Ga/177Lu-PSMA研发，将为国产创新核药诊疗一体化平台的建立及临床转化提供坚实的基础。

68Ga/177Lu- prostate specific membrane antigen (PSMA) is a theranostic drug that has attracted much attention in metastatic castration resistance prostate cancer (mCRPC) in recent years. 68Ga/177Lu-PSMA has key problems such as insufficient tumor uptake and internalization and medical isotope 68Ga/177Lu depended on foreign import completely. The research team had already carried out research and development of domestic 68Ga and 177Lu in the early stage, and found that the spatial structure of small molecule inhibitors of PSMA had an important impact on affinity and internalization rate. In this study, a series of small peptide derivatives of thiourea dipeptides will be synthesized by using thiourea dipeptide as skeleton structureand madifying branched chain amino of lysine and enhancing drug internalization with simulated peptide. The project team will take the lead in developing the domestic 68Ga/177Lu to label the small peptide derivatives and construct a novel theranostic radiopharmaceuticals for diagnosis and treatment targeted PSMA. The affinity, internalization rate and toxicity of labeling compounds will be verified by in vitro experiments. The biodistribution, metabolism, targeted imaging and therapy of the structure-activity relationship with PSMA inhibitors will be carried out through micro-PET/CT and SPECT/CT. The research and development of novel 68Ga/177Lu-PSMA with independent intellectual property rights will provide a solid foundation for the establishment and clinical transformation of domestic innovative radiopharmaceuticals diagnosis and treatment integration platform.