High-Spin Nitroxide Radical for Biomedical Imaging Applications

用于生物医学成像应用的高自旋氮氧自由基

• 批准号: 7588405
• 负责人: ANDRZEJ RAJCA
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7588405
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DESCRIPTION (provided by applicant): Nitroxide radicals are being investigated for many biological and biomedical applications, such as spin probes, antioxidants, radiation protectors, electron paramagnetic resonance imaging (EPRI), and magnetic resonance imaging (MRI). These applications rely mainly on the use of nitroxide monoradicals with the total spin quantum number (S) of 1/2. This R21 project will explore a new class of radicals, high-spin nitroxide diradicals with S = 1, for biomedical imaging applications. Because the signal intensity in MRI scales with the factor of S(S + 1) of paramagnetic agent, we expect that significant increases in sensitivity could be attained using high-spin S > 1/2 radicals as contrast agents. The specific hypothesis behind this proposal is that the S = 1 diradicals, especially the rigid scaffolds of S = 1 diradicals, can be made to possess adequate relaxivity and redox properties for functional MRI contrast agents. Diradicals and scaffolds of diradicals with rigid structure will be prepared by organic synthesis and their selected properties affecting 1H water relaxivity will be studied. Values of S(S + 1) will be measured by superconducting quantum interference device (SQUID) magnetometry and EPR spectroscopy. Rotational correlation times and electron spin relaxation times (T1 and T2) will be measured by EPR spectroscopy. Stability in the presence of ascorbate will be determined. Nitroxides with most promising relaxivities and redox properties will be subjected to an in vivo study. This information will provide an assessment of the key factors affecting the 1H water relaxivity of the nitroxide radicals, a foundation for our long term goal of the development of highly sensitive, functional, and safe MRI contrast agents based upon stable, redox-active high-spin nitroxide polyradicals with large values of S. Development of contrast agents based on organic compounds with strong paramagnetic properties will expand the frontier of biomedical imaging research. Various structural modifications of organic compounds for specific targeting and property tuning (magnetism, redox, solubility, toxicity) can be efficiently implemented by organic synthesis. Organic-based contrast agents will provide an alternative to metal-based agents, in which the property tuning is limited and their applications have been associated with the risk of exposure to highly toxic metal ions. Such organic-based agents should render safe, effective tools for early detection and diagnosis of diseases and for modern approaches to drug discovery. PUBLIC HEALTH RELEVANCE: Contrast agents based on organic compounds with strong paramagnetic properties provide alternative MRI contrast media to the metal-based agents, avoiding the risk factors associated with the release of highly toxic metal ions. This project will explore the feasibility of sensitive and safe contrast agents based on organic radicals. Such agents may ultimately render effective tools for early detection and diagnosis of diseases, and for modern approaches to drug discovery.

描述（由申请人提供）：正在研究许多生物学和生物医学应用，例如自旋探针，抗氧化剂，辐射保护剂，电子顺磁共振成像（EPRI）和磁共振成像（MRI）。这些应用主要依赖于使用氮氧化物单种子的使用，总自旋量子数为1/2。该R21项目将探索新的激进分子，用于生物医学成像应用的高旋转氮氧化物。由于MRI尺度中的信号强度与顺磁剂的S（S + 1）因子的因子，因此我们期望使用高旋转S> 1/2自由基作为对比剂的高自旋S> 1/2自由基可以实现敏感性的显着提高。该提议背后的特定假设是，可以提出S = 1个Diradicals，尤其是S = 1 Diradicals的刚性支架，以具有足够的放松性和功能性MRI对比剂的氧化还原性能。将通过有机合成及其影响1H水松弛度的其选定特性制备具有刚性结构的Diradicals和脚手架。 S（S + 1）的值将通过超导量子干扰装置（Squid）磁力测定法和EPR光谱法测量。旋转相关时间和电子自旋松弛时间（T1和T2）将通过EPR光谱测量。将确定在抗坏血酸盐存在下的稳定性。具有最有希望的松弛度和氧化还原特性的硝酸氧化物将接受体内研究。该信息将评估影响硝基自由基1H水松弛度的关键因素，这是我们长期目标的基础 研究。有机合成可以有效地实现有机化合物的各种有机化合物的结构修饰（磁性，氧化还原，溶解性，毒性）。基于有机的对比剂将提供基于金属的代理的替代方法，在该代理中，该特性调整有限，其应用与暴露于剧毒的金属离子的风险有关。这种有机的代理应为疾病的早期发现和诊断和现代药物发现方法提供安全，有效的工具。 公共卫生相关性：基于有机化合物具有强磁特性的对比剂为基于金属的代理提供了替代的MRI对比介质，从而避免了与释放剧毒的金属离子相关的危险因素。该项目将探索基于有机自由基的敏感和安全对比剂的可行性。这样的药物最终可能会提供有效的工具，用于早期检测和诊断疾病，以及现代的药物发现方法。