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.

抽象的 正电子发射断层扫描（PET）是一种灵敏的非侵入性成像技术，适用于诊断 以及各种疾病的分期。研究工作致力于开发肿瘤特异性 PET 成像 探针。 Zirconia-89 (89Zr, t1/2 = 78 h) 是一种正电子发射放射性核素，适用于以下物质的靶向 PET 成像： 使用生物半衰期相对较长的抗体来治疗肿瘤。 已知 89Zr 对骨矿物质羟基磷灰石 (HA) 具有高结合亲和力。 89Zr过早释放 临床 PET 成像过程中基于 89Zr 的生物分子可能导致骨中放射性物质大量积累 并产生包括骨髓毒性在内的放射毒性。还导致 89Zr 标记的 PET 示踪剂稳定性较差 图像质量下降和剂量测定不准确。因此，使用最佳螯合剂的稳定 89Zr 络合物 应用于安全且灵敏的免疫 PET 成像。还需要这种有效的螯合剂 在温和反应条件下用高能 89Zr 实际标记温度敏感抗体 最大限度地减少因抗体长时间暴露而造成的放射分解损伤。 89Zr 放射性药物用于癌症 PET 成像的临床潜力已在 大量的临床前和临床试验。目前，DFO（去铁胺 B）被用作 89Zr 的螯合，用 89Zr 标记的 DFO-抗体缀合物体内稳定性有限，导致高 在正常器官和组织（包括骨骼）中积累。 本研究的目的是创建基于结构独特的 89Zr 荧光新型螯合剂 PI 发明的配位基团和螯合化学。本次调查的创新之处包括 i) 开发对 89Zr 具有高结合亲和力的新小分子供体和 ii) 构建新配体 可以与 89Zr 形成高度稳定的复合物的平台和 iii) 新型自荧光螯合剂的应用 用于未结合 89Zr 和结合 89Zr 配合物的原位分析。 该提案的具体目标是 i) 合理设计对 89Zr(IV) 具有高亲和力的新型螯合化学；二） 具有结构变化的新螯合剂的文库合成； iii) 放射性标记新螯合剂的评估 89Zr 的动力学和络合物稳定性以及 89Zr 络合物的分光光度和荧光分析；四） 选择最佳（参见上述标准）螯合剂并将其与模型抗体结合； v) 生物分布， 使用肿瘤进行最佳螯合剂-抗体偶联物的药代动力学、代谢和 PET 成像研究 承载老鼠。完成这项研究旨在实现卓越的 89Zr 螯合化学，这将 致力于开发临床上可行的 PET 示踪剂，用于各种疾病的灵敏且安全的成像 使用不同的 α 或 β 发射放射性核素进行靶向放射治疗的精确剂量测定。