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

描述（由申请人提供）：拟定研究的目标是开发用于正电子发射断层扫描（PET）的锆-89（89 Zr）的稳健双功能螯合剂。抗体可以用PET放射性金属如89 Zr通过连接可以结合所讨论的放射性金属的螯合剂进行放射性标记。由此产生的成像剂对于癌症和其他疾病的诊断和分期非常有用。有证据表明，89 Zr在体内从与当前双功能螯合剂制成的络合物中释放。这种放射性物质的释放可能是有害的，并导致临床前研究期间89 Zr在小鼠骨骼中的积累。更稳定的螯合剂将减少游离89 Zr的释放，并产生更安全的放射性示踪剂。增加对骨积聚的关注将使基于89 Zr的PET成像剂的研究和应用更加广泛，这将导致对各种癌症类型的诊断和理解的改进。该项目包括锆配体的设计和合成;配体-金属结合的放射性标记和评价; 最合适的配体;以及用于PET成像的新型89 Zr-配体-抗体构建体的创建和最终生物学测试。配体的设计考虑到Zr需要硬供体配体并且优选八齿配位。选择用于开发的配体基于异羟肟酸盐、邻苯二酚和羟基吡啶酮结合基团，以符合Zr 4+的亲氧性。无论是裸配体还是双功能配体，配体的有机合成都需要深入的研究。将进行非放射性Zr配体物质的表征以及广泛的放射性标记实验，以评价各配体对锆的适用性。最佳配体将证明在与抗体相容的条件下清洁和有效的放射性标记以及高血清稳定性。最佳候选配体将被双官能化并与抗体缀合以用于进一步评价，包括小鼠中的PET成像和生物分布研究、免疫反应性测定和89 Zr-抗体构建体的稳定性研究。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，分子成像和转化研究的培训。除了研究开发，额外的培训将以课程，研讨会，专业会议，辅导机会和职业发展的形式提供。

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.