新型锆-89双功能螯合剂的设计、合成及生物学评价

89Zr-immuno-PET在筛选单抗治疗患者、评估单抗治疗疗效、进行个性化治疗等方面发挥着日益重要的作用。DFO是唯一临床使用的89Zr双功能螯合剂，但在体内存在不稳定因素。开发体内稳定性更好的新型89Zr双功能螯合剂对于推动89Zr抗体药物开发和临床转化具有重要的医学价值和社会意义。我们较早开展了新型89Zr双功能螯合剂研究，先后报道了新型大环89Zr双功能螯合剂FSC、DAFC和DSFC。本项目拟开展DAFC、DSFC与DFO、DFO*的平行对比研究，系统研究影响89Zr双功能螯合剂稳定性的因素以及双功能螯合剂对抗体靶向性质的影响程度，评估DAFC和DSFC在89Zr抗体药物开发和临床转化中的应用前景，同时建立基于DAFC和DSFC的与单克隆抗体偶联、标记、生物学评价的标准流程，为开发基于DAFC和DSFC的89Zr抗体药物提供研究范式。

In the field of Zirconium-89-based radiopharmaceuticals interest to develop novel bifunctional chelators to replace the only clinically used siderophore Deferoxamine (DFO) has increased over the last several years. Our previous studies demonstrated the high feasibility of DAFC and DSFC as bifunctional chelators for radiolabelling of biomolecules with Zirconium-89. However, due to the limited investigation of the in vivo stability of [89Zr]Zr-DAFC/DSFC-mAbs conjugates at the later time points, the application prospect of DAFC and DSFC as Zirconium-89 radiopharmaceuticals needs to be further evaluated and confirmed. This why in this project two constructs, namely DAFC-pPhe-NCS and DSFC-pPhe-NCS, will be synthesized, coupled to antibodies and then labeled with Zirconnium-89. Comparison between [89Zr]Zr-DAFC/DSFC and [89Zr]Zr-DFO/DFO* alone and after conjugation to antibodies will be performed. These investigations include in vitro and in vivo stability tests, partition coefficient, protein binding properties, BFC/mAbs ratio, internalization assays, immunoreactive fraction as well as biodistribution and µPET/CT imaging in normal and tumour-bearing mice. The project will investigate the factors affecting in vivo stability of 89Zr-chelators and evaluate the prospects of DAFC/DSFC as 89Zr radiopharmaeceuticals. Additionally the prospects for clinical translation of [89Zr]Zr-DAFC/DSFC-mAbs will be explored.