High-Spin Nitroxide Radical for Biomedical Imaging Applications

描述（由申请人提供）：正在研究氮氧自由基在许多生物和生物医学应用中的应用，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总自旋量子数（S）为1/2的氮氧单价自由基。这个R21项目将探索一类新的自由基，S = 1的高自旋氮氧双自由基，用于生物医学成像应用。由于MRI中的信号强度与顺磁剂的S（S +1）因子成比例，我们预期使用高自旋S> 1/2自由基作为造影剂可以获得灵敏度的显著增加。这一提议背后的具体假设是，S = 1双自由基，特别是S = 1双自由基的刚性支架，可以被制成具有足够的弛豫和氧化还原特性的功能性MRI造影剂。通过有机合成制备具有刚性结构的双自由基和双自由基支架，并研究其影响1H水弛豫率的选定性质。S（S +1）的值将通过超导量子干涉仪（SQUID）磁强计和EPR光谱测量。旋转相关时间和电子自旋弛豫时间（T1和T2）将通过EPR光谱测量。将测定抗坏血酸盐存在下的稳定性。具有最有前途的弛豫和氧化还原特性的氮氧化物将进行体内研究。该信息将提供影响氮氧自由基的1H水弛豫率的关键因素的评估，这是我们基于具有大S值的稳定的氧化还原活性高自旋氮氧多自由基开发高灵敏度、功能性和安全的MRI造影剂的长期目标的基础。基于具有强顺磁性的有机化合物的造影剂的开发将拓展生物医学成像研究的前沿。通过有机合成可以有效地实现用于特定靶向和性质调整（磁性、氧化还原、溶解度、毒性）的有机化合物的各种结构修饰。基于有机物的造影剂将提供基于金属的造影剂的替代方案，其中性质调节是有限的，并且它们的应用与暴露于高毒性金属离子的风险相关联。此类有机物制剂应该为疾病的早期检测和诊断以及药物发现的现代方法提供安全、有效的工具。 公共卫生相关性：基于具有强顺磁性的有机化合物的造影剂为基于金属的造影剂提供了替代MRI造影剂，避免了与释放高毒性金属离子相关的风险因素。本项目将探索基于有机自由基的敏感、安全的造影剂的可行性。这些药物最终可能成为疾病早期检测和诊断以及药物发现现代方法的有效工具。

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.