Development of Superior Chelation Chemistry for 89Zr-ImmunoPET Imaging

开发用于 89Zr-ImmunoPET 成像的高级螯合化学

• 批准号: 10256794
• 负责人: HYUN-SOON CHONG
• 金额: $ 38.65万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10256794
• 关键词: Affect; Affinity; Antibodies; BT 474; Binding; Biodistribution; Biological; Biological Markers; Blood; Bone Marrow; Breast; Chelating Agents; Chemistry; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Complex; Data; Deferoxamine; Development; Diagnosis; Discipline of Nuclear Medicine; Disease; Dissociation; Drug Kinetics; Durapatite; Edetic Acid; Evaluation; Female; Generations; Half-Life; Human; Image; Imaging Techniques; ImmunoPET; In Situ; In Vitro; Incubated; Investigation; Kinetics; LS174T colon cancer cell line; Label; Lead; Libraries; Ligands; Metabolism; Minerals; Modeling; Molecular Target; Mus; Nude Mice; Organ; Positron; Positron-Emission Tomography; Radiation Toxicity; Radioactivity; Radioimmunoconjugate; Radioisotopes; Radiolabeled; Radionuclide therapy; Radiopharmaceuticals; Reaction; Research; Roentgen Rays; Series; Serum; Staging; Structure; System; Targeted Radiotherapy; Technology; Temperature; Tissues; Toxic effect; Tracer; Trastuzumab; Variant; Woman; Xenograft procedure; Zirconium; absorption; antibody conjugate; authority; base; bone; cancer imaging; cellular imaging; chelation; clinical development; complex IV; design; dosimetry; experience; fluorodeoxyglucose; imaging agent; imaging probe; imaging study; immunoreactivity; improved; in vivo; in vivo evaluation; innovation; male; malignant breast neoplasm; metabolic abnormality assessment; metastatic colorectal; neoplastic cell; non-invasive imaging; novel; panitumumab; preclinical study; preclinical trial; premature; response; small molecule; specific biomarkers; tool; tumor; uptake

ABSTRACT Positron emission tomography (PET) is a sensitive and non-invasive imaging technique applicable to diagnosis and staging of various diseases. Research efforts have been devoted to develop tumor-specific PET imaging probes. Zirconium-89 (89Zr, t1/2 = 78 h) is a positron-emitting radionuclide suitable for targeted PET imaging of tumors using an antibody with a relatively long biological half-life. 89Zr is known to display a high binding affinity for bone mineral, hydroxylapatite (HA). Premature release of 89Zr from 89Zr-based biomolecules during clinical PET imaging can lead to high accumulation of radioactivity in bone and generate radiation toxicity including bone marrow toxicity. Less stable 89Zr-labeled PET tracers also result in diminished image quality and inaccurate dosimetry. Therefore, a stable 89Zr-complex using an optimal chelator should be employed for safe and sensitive immuno-PET imaging. Such an effective chelator is also required for practical labeling of a temperature-sensitive antibody with highly energetic 89Zr under mild reaction conditions to minimize radiolytic damage resulting from extended exposure of the antibody. Clinical potential of 89Zr-radiopharmaceuticals for PET imaging of cancers has been well demonstrated in numerous preclinical and clinical trials. While DFO (desferrioxamine B) is currently used as the standard for chelation of 89Zr, DFO-antibody conjugates labeled with 89Zr have limited in vivo stability resulting in high accumulation in normal organs and tissues, including bone. The objective of this investigation is to create fluorescent novel chelators of 89Zr built on the structurally unique coordinating groups and chelation chemistry that the PI invented. Innovative aspects of this investigation include i) development of new small molecule donors with high binding affinity for 89Zr and ii) construction of new ligand platforms that can form a highly stable complex with 89Zr and iii) application of novel self-fluorescent chelators for in situ analysis of unbound 89Zr and bound 89Zr complexes. Specific aims of this proposal are i) rational design of novel chelation chemistry with high affinity for 89Zr(IV); ii) library synthesis of the new chelators with structural variations; iii) evaluation of new chelators for radiolabeling kinetics and complex stability with 89Zr and spectrophotometric and fluorescent analysis of 89Zr complexes; iv) selection and conjugation of the best (see above criteria) chelators to a model antibody; v) biodistribution, pharmacokinetics, metabolism, and PET imaging studies of the best chelator-antibody conjugates using tumor bearing mice. Completion of this study is proposed to materialize superior 89Zr chelation chemistry that will contribute to development of clinically viable PET tracers for sensitive and safe imaging of various diseases and accurate dosimetry of targeted radiotherapy using different α- or β--emitting radionuclides.

摘要