Library Synthesis and Screening of Eu(II)-Based Contrast Agents

基于 Eu(II) 的造影剂的文库合成和筛选

• 批准号: 10093042
• 负责人: MATTHEW J ALLEN
• 金额: $ 31.56万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093042
• 关键词: Area; Automobile Driving; Binding; Chemicals; Chemistry; Clinical; Complex; Contrast Media; Data; Development; Diagnosis; Diagnostic; Disease; Ensure; Environment; Europium; Exhibits; Foundations; Future; Glutathione; Goals; Health; Homeostasis; Human; Human Development; Hypoxia; Image; Investments; Ions; Kinetics; Knowledge; Libraries; Ligand Binding; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Medical; Medicine; Metals; Mission; Modification; Monitor; Necrosis; Outcome; Oxidants; Oxidation-Reduction; Oxides; Precipitation; Property; Public Health; Rapid screening; Research; Research Project Grants; S Phase; Selection for Treatments; Solid; Structure; System; Testing; Thermodynamics; Tissue Differentiation; Translations; Tumor Tissue; United States National Institutes of Health; base; cancer diagnosis; cancer therapy; contrast enhanced; design; experimental study; human disease; improved; in vivo; innovation; interest; novel therapeutics; oxidation; preclinical study; response; screening; small molecule; therapy development; therapy outcome; tool; trend; tumor; tumor hypoxia

There is a great need for contrast agents for magnetic resonance imaging (MRI) that respond to changes in redox environment to enable the facile monitoring of responses to new therapies, to guide cancer treatment selection, to image early responses for driving treatment development, and to enable the testing of hypotheses relevant to the collective fundamental understanding between redox environment and human health. The long- term goal of the research project is to develop positive contrast agents for MRI to fill this void in diagnostic medicine by focusing on EuII-containing complexes that are among the most promising areas of study. The overall objective of this application is to establish the groundwork necessary for translation of new Eu-based complexes into useful redox-responsive contrast agents by assembling and screening a library of EuII- and EuIII-containing complexes for their thermodynamic stability, kinetic inertness, and relaxivity. The rationale that underpins the proposed research is that EuII can be stabilized against oxidation and rendered non-toxic in vivo through ligand modification, as recently demonstrated; that the ideal ligand system will coordinate both EuII and EuIII; and that ligands that bind both oxidation states can be rationally designed with the information gained by studying a library of complexes. The expected outcome of this proposal is a great strengthening of the chemical foundation for the development of redox-responsive, Eu-based complexes for use as contrast agents in MRI. This outcome is expected to have a positive impact by contributing to the NIH's mission in the diagnosis of human diseases and development of new therapies. The objective of the proposal is expected to be achieved by pursuing three specific aims: (1) to assemble a library of ligands composed of synthesized cryptands and commercially available noncryptand ligands; (2) to screen ligands with EuII and with GdIII for T1- shortening indicative of complex formation; and (3) to characterize the thermodynamic stability, kinetic inertness, and relaxivity of EuII- and EuIII-containing complexes. The new Eu-based probes will be significant because they are expected to enable changes in redox environments resulting from therapies to be imaged, consequently, aiding in treatment development and selection and increasing the basic understanding of the relationship between redox homeostasis and human health. Furthermore, because redox homeostasis is relevant to a wide-range of diseases, this proposal is expected to maximize returns in many other investments of the NIH.

磁共振成像（MRI）非常需要对比度，以应对变化 氧化还原环境可以轻松监测对新疗法的反应，以指导癌症治疗 选择，图像提前响应以推动治疗开发，并能够测试假设 与氧化还原环境与人类健康之间的集体基本理解有关。长期 研究项目的术语目标是为MRI开发阳性对比度，以填补这一空隙的诊断。 通过专注于最有希望的研究领域之一的含EUII的复合物。这 该应用程序的总体目的是建立翻译基于新的欧盟所需的基础 通过组装和筛选EUII-和 具有热力学稳定性，动力学惰性和松弛性的含EUIII复合物。理由 拟议的研究基础是，EUII可以稳定在氧化中，并在体内引起无毒 通过最近证明的配体修饰；理想的配体系统将协调EUII和 euiii;并且结合两种氧化态的配体可以通过由 研究复合物库。该提案的预期结果是对 化学基础，用于开发氧化还原响应性的基于欧盟的复合物作为对比剂 在MRI中。预计该结果将通过为NIH的使命做出积极影响 人类疾病的诊断和新疗法的发展。该提议的目的有望 可以通过追求三个特定目标来实现：（1）组装由合成的配体库 加密和市售的非cryptand配体； （2）用EUII筛选配体和GDIII进行T1- 缩短表明复杂形成的指示； （3）表征热力学稳定性，动力学 Euii和含EUIII的惰性复合物的惰性和放松性。新的基于欧盟的探针将是重要的 因为期望它们能够成像疗法导致的氧化还原环境变化，所以 因此，协助治疗开发和选择，并提高对 氧化还原稳态与人类健康之间的关系。此外，因为氧化还原稳态是 该提案与广泛疾病有关，预计该提案将最大化许多其他投资的回报 NIH。