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 正电子发射断层扫描（PET）是一种敏感和非侵入性的成像技术，适用于诊断 和各种疾病的分期。研究工作一直致力于开发肿瘤特异性PET成像 probes.锆-89（89 Zr，t1/2 = 78 h）是一种正电子发射放射性核素，适用于靶向PET成像， 使用具有相对长的生物半衰期的抗体治疗肿瘤。 已知89 Zr对骨矿物质羟基磷灰石（HA）显示出高结合亲和力。89 Zr过早释放 在临床PET成像过程中，89 Zr基生物分子的放射性可导致骨中放射性的高积累 并产生包括骨髓毒性在内的辐射毒性。不太稳定的89 Zr标记的PET示踪剂也导致 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的89 Zr-络合物 应用于安全和敏感的免疫PET成像。也需要这种有效的螯合剂， 在温和的反应条件下用高能89 Zr对温度敏感性抗体进行实际标记， 最小化由抗体的延长暴露导致的辐射分解损伤。 89 Zr-放射性药物用于癌症PET成像的临床潜力已经在 许多临床前和临床试验。虽然DFO（去铁胺B）目前被用作 89 Zr的螯合，用89 Zr标记的DFO-抗体缀合物具有有限的体内稳定性，导致高的 在正常器官和组织中积累，包括骨骼。 本研究的目的是建立在结构独特的89 Zr的荧光新螯合剂， 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89 Zr具有高结合亲和力的新的小分子供体，和ii）构建新的配体 可以与89 Zr形成高度稳定的络合物的平台和iii）新型自荧光螯合剂的应用 用于原位分析未结合的89 Zr和结合的89 Zr络合物。 该提议的具体目的是i）合理设计对89 Zr（IV）具有高亲和力的新型螯合化学; ii） 具有结构变化的新螯合剂的文库合成; iii）用于放射性标记的新螯合剂的评价 动力学和与89 Zr的络合物稳定性以及89 Zr络合物的分光光度和荧光分析; iv） 选择最佳（参见上述标准）螯合剂并将其与模型抗体偶联; v）生物分布， 使用肿瘤的最佳螯合剂-抗体缀合物的药代动力学、代谢和PET成像研究 产鼠本研究的完成旨在实现上级89 Zr螯合化学， 有助于开发临床可行的PET示踪剂，用于各种疾病的灵敏和安全成像， 使用不同的α或β放射性核素进行靶向放射治疗的精确剂量测定。