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: 10330634
• 负责人: MATTHEW J ALLEN
• 金额: $ 10万
• 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/10330634
• 关键词: Area; Automobile Driving; Chemicals; Complex; Contrast Media; Development; Diagnosis; Diagnostic; Disease; Environment; Europium; Foundations; Goals; Health; Homeostasis; Human; Human Development; Image; Investments; Kinetics; Knowledge; Libraries; Ligand Binding; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Medicine; Mission; Modification; Monitor; Necrosis; Outcome; Oxidation-Reduction; Public Health; Research; Research Project Grants; Selection for Treatments; System; Testing; Thermodynamics; Translations; United States National Institutes of Health; base; cancer therapy; design; human disease; improved; in vivo; novel therapeutics; oxidation; response; screening; therapy development; therapy outcome; tumor

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) 非常需要能够响应变化的造影剂 氧化还原环境能够轻松监测对新疗法的反应，指导癌症治疗 选择，对推动治疗开发的早期反应进行成像，并能够检验假设 与氧化还原环境和人类健康之间的集体基本理解相关。长- 该研究项目的长期目标是开发 MRI 阳性造影剂，以填补诊断领域的空白 重点关注含 EuII 的复合物，这是最有前途的研究领域之一。这 该应用程序的总体目标是为翻译新的欧盟语言奠定必要的基础 通过组装和筛选 EuII- 和 的文库，将复合物转化为有用的氧化还原响应造影剂 含 EuIII 的配合物具有热力学稳定性、动力学惰性和弛豫性。理由是 所提出的研究的基础是 EuII 可以稳定地抗氧化并使其在体内无毒 正如最近所证明的，通过配体修饰；理想的配体系统将同时协调 EuII 和 欧III;并且结合两种氧化态的配体可以根据获得的信息进行合理设计 研究复合体图书馆。该提案的预期成果是大大加强 开发用作造影剂的氧化还原响应性铕基复合物的化学基础 在核磁共振成像中。这一成果预计将通过为 NIH 的使命做出贡献而产生积极影响。 人类疾病的诊断和新疗法的开发。该提案的目标预计是 通过追求三个具体目标来实现：（1）组装由合成的配体组成的配体库 穴状配体和市售的非穴状配体配体； (2) 用EuII和GdIII筛选T1-的配体 缩短表明复杂的形成； (3) 表征热力学稳定性、动力学 含 EuII 和 EuIII 配合物的惰性和弛豫性。新的基于欧盟的探测器将具有重要意义 因为它们有望使治疗引起的氧化还原环境的变化得以成像， 因此，有助于治疗的开发和选择，并增加对治疗的基本了解 氧化还原稳态与人类健康之间的关系。此外，由于氧化还原稳态 该提案与多种疾病相关，预计将使许多其他投资的回报最大化 美国国立卫生研究院的。