New Ligands for Radioimmunotherapy and MRI of Cancer

描述(由申请人提供)：开发足够的配体来有效地持有金属是提高放射免疫治疗(RIT)和磁共振成像(MRI)疗效的关键步骤。这项拟议研究的长期目标是开发临床上可行的配体，这些配体可以直接应用于RIT和MRI这两个癌症研究领域。在目前的提案中，我们将把我们的努力集中在关于大环配体设计的两个具体目标上，这两个目标可能满足积极的RIT和MRI临床探索的迫切需要。 第一个具体目标是探索一种双峰结合方法，以产生更好的双功能配体，从而有效地结合有希望的放射性核素，用于RIT。这一目标是基于这样的假设，即同时使用大环腔和非环侧链结合基团的协同结合可以在保持高水平络合稳定性的同时提供增强的金属络合动力学。我们的初步数据表明，其中一个新的配体，NOETA首次与Y-86结合，Y-86是RIT的重要放射性金属，具有良好的动力学和体内稳定性。我们将进一步测试双峰结合方法，方法是制备用于RIT应用的双功能配体，并评估双功能配体与各种放射性金属(如Y-90、Bi-213和Ac-225)的络合动力学和热力学。 第二个具体目的是研究在常规造影剂中加入天然类固醇(S)如何影响肿瘤特异性磁共振造影剂的标准，即高和延长的信号强度、体内稳定性、良好的细胞渗透性、完全清除和高靶向性。这一目的是基于这样的假设，即在常规MR造影剂中加入类固醇部分促进类固醇转运体和共轭造影剂之间的非共价相互作用。新的配体NOETA还显示了磁共振信号强度和体内稳定性，可与临床批准的非特异性MRI试剂相媲美。利用该配体作为支架，我们将研究附着的类固醇作为肿瘤特异性磁共振造影剂的肿瘤靶向载体的潜力。 拟议的研究结果将有助于开发更好的MRI和RIT药物，这将极大地加强这两种方式的临床探索，并直接使癌症患者受益。

DESCRIPTION (provided by applicant): The development of the adequate ligands to effectively hold metals is a critical step for enhancing the efficacy of radioimmunotherapy (RIT) and magnetic resonance imaging (MRI). The long-term objective of the proposed research is to develop clinically viable ligands that have direct applications in two cancer research fields, RIT and MRI. In the current proposal we will focus our effort on two specific aims regarding the design of macrocyclic ligands that may address the pressing needs for active clinical exploration of RIT and MRI. The first specific aim is to explore a bimodal binding approach to generate better bifunctional ligands to efficiently bind promising radionuclides for use in RIT. This aim is based on the hypothesis that the cooperative binding using both a macrocyclic cavity and an acyclic pendant binding group may provide enhanced kinetics in metal complexation while maintaining a high level of complex stability. Our preliminary data indicate that one of the new ligands, NOETA binds Y-86, an important radioactive metal for RIT for the first time, with excellent kinetics and in vivo stability. We will further test the bimodal binding approach by preparing bifunctional ligands for RIT applications, and by evaluating complexation kinetics and thermodynamics of the bifunctional ligands with a variety of radioactive metals for RIT such as Y-90, Bi-213 and Ac-225. The second specific aim is to investigate how incorporation of naturally occurring steroid(s) into the conventional contrast agent affects criteria of tumor-specific MR contrast agents, i.e., high and extended signal intensity, in vivo stability, good cell permeation, complete clearance, and high target specificity. This aim is based on the hypothesis that a steroid moiety incorporated into the conventional MR contrast agent promotes non-covalent interactions between the steroid transporters and the conjugated contrast construct. The new ligand NOETA also has shown MR signal intensity, and in vivo stability comparable to the clinically approved non-specific MRI agents. Using this ligand as a scaffold, we will investigate the potential of the attached steroid as a tumor targeting vector of tumor-specific MR contrast agents. The results of the proposed research will contribute to the development of better drugs for both MRI and RIT, which will greatly enhance clinical exploration of both modalities, and directly benefit cancer patients.