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: 10377906
• 负责人: MATTHEW J ALLEN
• 金额: $ 32.01万
• 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377906
• 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; rational design; 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.

对磁共振成像(MRI)的造影剂有很大的需求，以响应 氧化还原环境，能够方便地监测对新疗法的反应，以指导癌症治疗 选择，以描绘推动治疗开发的早期反应，并使假说能够得到检验 与氧化还原环境与人类健康之间的集体基本理解有关。长的- 该研究项目的长期目标是开发用于MRI的阳性造影剂，以填补这一诊断空白 通过重点研究包含EuII的络合物，这是最有希望的研究领域之一。这个 这项申请的总体目标是为翻译新的欧盟版奠定必要的基础 通过组装和筛选EuII-和EuII-And文库成为有用的氧化还原反应对比剂 含EuIII的络合物的热力学稳定性、动力学惰性和松弛性能。其基本原理是 支持这项拟议的研究的是，EuII在体内可以稳定地抵抗氧化并变得无毒。 通过配体修饰，正如最近证明的那样，理想的配体系统将协调EuII和EuII EuIII；结合这两个氧化态的配体可以根据从 研究一个复合体的图书馆。这项提议的预期结果是极大地加强了 用于对比剂的氧化还原响应型Eu基络合物开发的化学基础 在核磁共振中。这一结果预计将对美国国家卫生研究院的任务产生积极影响 人类疾病的诊断和新疗法的开发。该提案的目标预计将是 通过追求三个具体目标来实现：(1)组装一个由合成的 密码子和商用非密码子配体；(2)使用EuII和GdIII筛选T1- 缩写指示络合物的形成；以及(3)表征热力学稳定性、动力学 含EuII和EuIII的络合物的惰性和松弛性能。新的欧盟调查将具有重要意义 因为它们有望使治疗引起的氧化还原环境中的变化能够被成像， 因此，有助于治疗的开发和选择，并增加对 氧化还原动态平衡与人类健康的关系此外，因为氧化还原动态平衡是 这项建议与广泛的疾病相关，预计将使许多其他投资获得最大回报 美国国立卫生研究院的。

项目成果

Versatile Para-Substituted Pyridine Lanthanide Coordination Complexes Allow Late Stage Tailoring of Complex Function.

• DOI: 10.1002/chem.202103243
• 发表时间: 2021-12-20
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Starck M;Fradgley JD;De Rosa DF;Batsanov AS;Papa M;Taylor MJ;Lovett JE;Lutter JC;Allen MJ;Parker D
• 通讯作者: Parker D