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

Zirconia-89：放射化学和配体设计以改进 PET 应用

• 批准号: 8877461
• 负责人: Melissa A Deri
• 金额: $ 2.86万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877461
• 关键词: Accounting; Acute; Animals; Antibodies; Autoradiography; Behavior; Binding; Biodistribution; Biological; Biological Assay; Biological Testing; Cancer Biology; Catechols; Cations; Chelating Agents; Chemicals; Complex; Custom; Deferoxamine; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Dose; Drug Kinetics; Evaluation; Exhibits; Filtration; Goals; Health; High Pressure Liquid Chromatography; Image; In Vitro; Investigation; Kinetics; Laboratories; Lead; Life; Ligands; Mass Spectrum Analysis; Memorial Sloan-Kettering Cancer Center; Mentors; Metals; Modeling; Molecular Models; Molecular Sieve Chromatography; Mus; NMR Spectroscopy; Nature; Organic Synthesis; Patients; Positron-Emission Tomography; Property; Radioactive; Radioactivity; Radiochemistry; Radioisotopes; Radiolabeled; Research; Research Project Grants; Risk; Safety; Series; Serum; Structure; System; Techniques; Thermodynamics; Tissues; Tracer; Training; Translational Research; Vertebral column; Work; X-Ray Computed Tomography; Zirconium; base; bone; cancer imaging; cancer type; career development; chelation; college; density; design; disease diagnosis; experience; hydroxamate; imaging agent; immunoreactivity; improved; in vivo; molecular imaging; molecular modeling; mouse model; novel; pre-clinical; preclinical study; radiation absorbed dose; radiochemical; radiotracer; research and development; research study; symposium; theories; tumor; uptake; zirconium oxide

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.

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) 的锆 89 (89Zr) 的稳健双功能螯合剂。通过连接可以结合相关放射性金属的螯合剂，可以用 PET 放射性金属（例如 89Zr）对抗体进行放射性标记。由此产生的显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，目前的双功能螯合剂制成的复合物会在体内释放 89Zr。这种放射性物质的释放可能有害，并会导致临床前研究期间 89Zr 在小鼠骨骼中积聚。更稳定的螯合剂将减少游离 89Zr 的释放，并产生更安全的放射性示踪剂。增加对骨积累的关注将使基于 89Zr 的 PET 显像剂得到更广泛的研究和应用，从而改善对各种癌症类型的诊断和了解。该项目需要设计和合成适合锆的配体；配体-金属结合的放射性标记和评估；双功能化 最适合的配体；以及用于 PET 成像的新型 89Zr-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更喜欢八齿配位。选择用于开发的配体基于异羟肟酸、儿茶酚和羟基吡啶酮结合基团，以符合 Zr4+ 的亲氧性质。配体的有机合成需要大量开发，无论是裸配体还是双功能配体。将进行非放射性锆配体的表征以及广泛的放射性标记实验，以评估每种配体对锆的适用性。最佳配体将在与抗体兼容的条件下表现出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功能化并与抗体缀合，以进行进一步评估，包括 PET 成像和小鼠生物分布研究、免疫反应性测定以及 89Zr 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方面的培训。除了研究开发之外，还将以课程、研讨会、专业会议、指导机会和职业发展的形式提供额外的培训。