Zirconium-89: Radiochemistry and Ligand Design toward Improved PET Applications

描述(由申请人提供)：拟议研究的目标是开发用于正电子发射断层扫描(PET)的坚固的双功能螯合剂。抗体可以通过连接能够结合所讨论的放射性金属的螯合剂来标记PET放射性金属，如89Zr。由此产生的显像剂对癌症和其他疾病的诊断和分期非常有用。有证据表明，用目前的双功能络合剂制成的络合物中有89Zr在体内释放。这种放射性物质的释放可能是有害的，并导致89Zr在临床前研究期间在小鼠的骨骼中积累。更稳定的螯合剂将减少游离的89Zr的释放，并导致更安全的放射性示踪剂。增加对骨积累的关注将使以89Zr为基础的PET显像剂得到更广泛的研究和应用，从而提高对各种癌症类型的诊断和了解。该项目包括设计和合成专为锆量身定做的配体；放射性标记和评估配体-金属结合； 最合适的配体；以及用于PET成像的新型89Zr配体抗体构建物的创建和最终的生物测试。配体的设计考虑到了Zr需要一个硬给体配体，并倾向于八齿配位。选择用于开发的配体是基于异羟甲酸酯、邻苯二酚和羟基吡啶酮结合基团，这与Zr4的亲氧性保持一致。无论是裸配体还是双功能配体，有机合成都需要深入研究。将对非放射性的锆配位体进行表征，并进行广泛的放射性标记实验，以评估每种配位体对锆的适宜性。一个最佳的配基将在与抗体相容的条件下展示清洁和有效的放射性标记，以及高血清稳定性。最佳的候选配体将被双官能化并与抗体结合以进行进一步的评估，包括PET成像和在小鼠中的生物分布研究、免疫反应性分析以及89Zr-抗体结构的稳定性研究。该项目将作为纪念斯隆-凯特琳癌症中心和亨特学院之间的博士培训经验的一部分进行。它将包括合成有机、无机和放射化学以及癌症生物学、分子成像和翻译研究方面的培训。除了研究开发，还将通过课程作业、研讨会、专业会议、指导机会和职业发展等形式提供额外的培训。

DESCRIPTION (provided by applicant): The goal of the proposed research is to develop robust bifunctional chelators for the use of zirconium-89 (89Zr) for Positron Emission Tomography (PET). Antibodies can be radiolabeled with PET radiometals, such as 89Zr, through the attachment of a chelator which can bind the radiometal in question. The resulting imaging agents are extremely useful for the diagnosis and staging of cancer and other diseases. There is evidence of release of 89Zr in the body from complexes made with the current bifunctional chelator. This release of radioactive material can be harmful and leads to the accumulation of 89Zr in the bones of mice during preclinical studies. A more stable chelator will reduce the release of free 89Zr and result in safer radiotracers. Increasing the concern over bone accumulation will enable the more widespread investigation and application of 89Zr-based PET imaging agents which will lead to improvements in the diagnosis and understanding of various cancer types. This project entails the design and synthesis of ligands tailored to zirconium; the radiolabeling and evaluation of the ligand-metal binding; the bifunctionalization of the best suited ligands; and the creation and ultimate biological testing of novel 89Zr-ligand-antibody constructs for PET imaging. The design of the ligands takes into account that Zr requires a hard donor ligand and prefers octadentate coordination. The ligands chosen for development are based on hydroxamate, catechol, and hydroxypyridinone binding groups in keeping with the oxophillic nature of Zr4+. The organic synthesis of the ligands will require intensive development, both for the bare ligands and the bifunctional ligands. The characterization of the non-radioactive Zr-ligand species will be carried out as well as extensive radiolabeling experiments to evaluate the suitability of each ligand for zirconium. An optimal ligand will demonstrate clean and efficient radiolabeling at conditions compatible with antibodies as well as high serum stability. The best candidate ligands will be bifunctionalized and conjugated to antibodies for further evaluation including PET imaging and biodistribution studies in mice, immunoreactivity assays, and stability studies of the 89Zr-antibody construct. This project will be undertaken as part of the doctoral training experience between Memorial Sloan-Kettering Cancer Center and Hunter College. It will include training in synthetic organic, inorganic, and radiochemistry as well as cancer biology, molecular imaging, and translational research. Beyond the research development, additional training will be provided in the form of coursework, seminars, professional conferences, mentoring opportunities, and career development.