High-Spin Nitroxide Radical for Biomedical Imaging Applications

描述(申请人提供)：氮氧化物自由基正在被研究用于许多生物和生物医学应用，如自旋探针、抗氧化剂、辐射防护剂、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总自旋量子数(S)为1/2的氮氧化物的使用。这个R21项目将探索一类新的自由基-S=1的高自旋氮氧化物双自由基，用于生物医学成像应用。由于磁共振成像的信号强度与顺磁剂的S(S+1)的因子成比例，我们预计使用高自旋的S和1/2自由基作为造影剂可以显著提高灵敏度。这一建议背后的具体假设是，可以使S=1个双自由基，特别是S=1个双自由基的刚性支架具有足够的驰豫和氧化还原性能，作为功能性磁共振造影剂。采用有机合成的方法制备刚性结构的双基及其骨架，研究它们的选择性质对1H水弛豫性能的影响。S(S+1)的值将用超导量子干涉装置(SQUID)磁测量和电子顺磁共振光谱测量。转动相关时间和电子自旋弛豫时间(t1和t2)将由EPR谱测量。在抗坏血酸存在下的稳定性将被测定。具有最有希望的松弛和氧化还原性能的氮氧化物将进行体内研究。这些信息将提供对影响氮氧自由基1H水弛豫度的关键因素的评估，为我们开发基于稳定、氧化还原活性的高自旋氮氧自由基的高灵敏、功能和安全的磁共振造影剂的长期目标奠定了基础。通过有机合成可以有效地对有机化合物进行各种结构修饰，以实现特定的靶向和性质调节(磁性、氧化还原、溶解性、毒性)。有机基造影剂将为金属基造影剂提供一种新的选择，因为金属基造影剂的性能调节受到限制，而且其应用存在暴露于剧毒金属离子的风险。这种有机试剂应成为早期发现和诊断疾病以及采用现代药物发现方法的安全、有效的工具。 与公众健康相关：基于具有强烈顺磁性的有机化合物的造影剂为金属基造影剂提供了替代的MRI造影剂，避免了与剧毒金属离子释放相关的风险因素。该项目将探索基于有机自由基的敏感和安全的造影剂的可行性。这些药物最终可能为疾病的早期发现和诊断以及药物发现的现代方法提供有效的工具。

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.