Development of Superior Chelation Chemistry for 89Zr-ImmunoPET Imaging

摘要 正电子发射断层扫描(PET)是一种敏感的、无创的成像技术，适用于诊断 以及各种疾病的分期。人们一直致力于开发肿瘤特异性PET成像技术 探测器。~(89)Zr(T_(1/2)=78h)是一种发射正电子的放射性核素，适用于靶向正电子发射计算机断层扫描 肿瘤使用的抗体具有相对较长的生物半衰期。 已知89Zr与骨矿羟基磷灰石(HA)具有很高的结合亲和力。~(89)Zr过早释放 临床正电子发射计算机断层扫描可能导致放射性在骨中的高积聚 并产生包括骨髓毒性在内的辐射毒性。不太稳定的89Zr标记的PET示踪剂也会出现 图像质量下降和剂量测量不准确。因此，使用最佳的络合剂可以得到稳定的~(89)Zr-络合物 应用于安全和敏感的免疫-PET成像。这种有效的螯合剂也是需要的 在温和反应条件下用高能~(89)Zr标记温敏抗体 最大限度地减少因长时间暴露抗体而造成的辐射损害。 ~(89)Zr-放射性药物用于肿瘤PET成像的临床潜力已在#年得到很好的证明。 大量的临床前和临床试验。而DFO(去铁胺B)目前被用作 ~(89)Zr标记的DFO-抗体偶联物与~(89)Zr、DFO的络合作用在体内稳定性有限，导致高 蓄积在正常器官和组织中，包括骨骼。 这项研究的目的是在结构独特的基础上创造出新型的荧光螯合剂89Zr。 PI发明的配位基团和络合化学。这项调查的创新方面包括 1)开发对~(89)Zr具有高结合亲和力的新的小分子供体；2)构建新的配体 可与~(89)Zr形成高度稳定络合物的平台及III)新型自荧光络合剂的应用 用于未结合的~(89)Zr和结合的~(89)Zr络合物的原位分析。 这一建议的具体目的是：1)合理设计对89Zr(IV)具有高亲和力的新型螯合化学；2) 具有结构变化的新型螯合剂的文库合成；iii)用于放射性标记的新型螯合剂的评价 ~(89)Zr的动力学和络合物稳定性及~(89)Zr络合物的分光光度和荧光分析 最好的(见上述标准)螯合剂与模型抗体的选择和偶联；v)生物分布， 使用肿瘤的最佳螯合剂-抗体结合物的药代动力学、代谢和PET成像研究 生老鼠。这项研究的完成是为了实现更好的89Zr螯合化学，这将 帮助开发临床上可行的PET示踪剂，用于各种疾病的敏感和安全成像 使用不同发射放射性核素的α或β进行靶向放射治疗的精确剂量测定。

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.