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）：拟议的研究的目的是开发强大的双功能螯合剂，用于使用锆89（89ZR）进行正电子发射断层扫描（PET）。可以通过连接螯合剂来结合所讨论的辐射量，可以用PET辐射仪（例如89ZR）进行放射性标记。所得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，体内由当前双功能螯合剂制成的复合物中释放了89zR。放射性材料的这种释放可能是有害的，并导致临床前研究中小鼠骨骼中89ZR的积累。更稳定的螯合剂将减少自由89ZR的释放，并导致更安全的放射性示例。增加对骨骼积累的关注将使基于89ZR的PET成像剂进行更广泛的研究和应用，这将改善各种癌症类型的诊断和理解。该项目需要设计和合成专为锆的配体；配体金属结合的放射标记和评估；双功能的 最适合的配体；以及用于宠物成像的新型89ZR-配合抗体构建体的创建和最终生物学测试。配体的设计考虑了ZR需要硬体配体，并且更喜欢八位型配位。选择用于发育的配体基于羟氨酸，儿茶酚和羟基吡啶酮结合基的基于Zr4+的氧硅质性质。配体的有机合成将需要对裸配体和双功能配体进行密集发育。将进行非放射性ZR配体物种的表征以及广泛的放射标记实验，以评估每个配体对锆的适合性。最佳配体将在与抗体兼容以及高血清稳定性的条件下表现出清洁有效的放射性标记。最好的候选配体将被双功能化并与抗体结合，以进行进一步评估，包括小鼠的PET成像和生物分布研究，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 - 凯特林癌症中心与亨特学院之间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。除研究开发外，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其他培训。