Redox Imaging using Nitroxides and MRI

使用氮氧化物和 MRI 进行氧化还原成像

• 批准号: 8349161
• 负责人: James Mitchell
• 金额: $ 55.7万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349161
• 关键词: Aging-Related Process; Anatomy; Antioxidants; Area; Biochemical; Blood - brain barrier anatomy; Brain; Cataract; Cell membrane; Cells; Clinical; Contrast Media; Development; Diagnosis; Diagnostic; Diagnostic Imaging; Drug Kinetics; Electron Spin Resonance Spectroscopy; Evaluation; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Hydroxylamine; Image; Image Analysis; Imaging Techniques; Inflammatory; Magnetic Resonance Imaging; Measures; Medical Research; Molecular; Monitor; Mus; Myocardium; Neurocognitive; Normal tissue morphology; Oxidation-Reduction; Oxygen; Physiological; Property; Radiation; Radiation-Protective Agents; Reperfusion Injury; Stroke prevention; Time; Tissues; Treatment Efficacy; Variant; base; in vivo; neoplastic; prognostic; tempol; tumor

Summary Nitroxides are efficient antioxidants and radiation protectors and recent studies have shown that they can be used as functional MRI contrast probes. Because nitroxides are paramagnetic their presence in tissue can be monitored non-invasively by MRI. Further the disappearance of nitroxide induced MR intensity enhancement in tissue is a result of intracellular reduction of the nitroxides to the hydroxylamine. By following the rate of reduction of the nitroxide in tissue the redox rate can be determined. This property distinguishes nitroxides as functional MR contrast agents revealing information about the intracellular redox capacity of cells/tissues. An extensive study of nitroxide reduction rates in different normal tissues in mice and various types of tumors using a 5-membered ring nitroxide (3CP) and a 6-membered ring nitroxide, Tempol has been completed. Reduction rates were found to vary greatly among normal tissues and selected tumor types. In general, reduction rates were slower for the five membered nitroxide than the six membered nitroxide. It was found that 3CP was reduced 3 to 11 times slower (depending on the tissue) than Tempol in vivo and that maximum tissue concentration varies substantially between tissues (0.6 to 7.2 mM). For a given tissue, the maximum concentration usually did not vary between the two nitroxides. Furthermore, using electron paramagnetic resonance spectroscopy, we showed that the nitroxide reduction rate depends only weakly on cellular oxygen concentration in the oxygen range expected in vivo. These observations, taken with the marked variation in nitroxide reduction rates observed between tissues, suggest that tissue oxygen concentration is not a major determinant of the nitroxide reduction rate in vivo. For the purpose of redox imaging, 3CP was shown to be an optimal choice based on the achievable concentrations and bioreduction observed in vivo. Another five membered ring nitroxide (designated 23c) was found to provide T1 contrast in the brain, suggesting that nitroxides penetrate the blood brain barrier. Pharmacokinetic studies revealed that 23c is an effective redox imaging agent in the mouse brain, and that 23c may allow functional imaging of the myocardium as well. 23c may be useful in studies assessing radiation-induced neurocognitive damage and other damage to the brain including ischemia reperfusion injury. This nitroxide was also found to be a very potent protector against radiation damage in normal tissues (mouse). Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia reperfusion injury studies, stroke, prevention of cataracts, inflammatory processes, and aging. Nitroxide based MRI evaluation may have clinical utility in defining the above-mentioned conditions.

摘要氮氧自由基是有效的抗氧化剂和辐射保护剂，最近的研究表明，它们可以用作功能性MRI造影剂探针。由于氮氧自由基是顺磁性的，因此可以通过MRI非侵入性地监测其在组织中的存在。此外，组织中氮氧化物诱导的MR强度增强的消失是氮氧化物在细胞内还原为羟胺的结果。通过跟踪组织中氮氧化物的还原速率，可以确定氧化还原速率。该特性将氮氧化物区分为功能性MR造影剂，揭示了关于细胞/组织的细胞内氧化还原能力的信息。使用5元环氮氧自由基（3CP）和6元环氮氧自由基Tempol对小鼠不同正常组织和各种类型肿瘤的氮氧自由基还原率进行了广泛研究。 发现正常组织和选定的肿瘤类型之间的减少率差异很大。 一般来说，五元氮氧自由基的还原速率比六元氮氧自由基慢。发现3CP在体内比Tempol降低慢3至11倍（取决于组织），并且最大组织浓度在组织之间变化很大（0.6至7.2 mM）。对于给定的组织，两种氮氧化物的最大浓度通常没有变化。此外，使用电子顺磁共振光谱，我们表明，氮氧化物还原率只依赖于微弱的细胞氧浓度在体内预期的氧范围内。这些观察结果表明，组织间观察到的氮氧化物还原率的显著变化表明，组织氧浓度不是体内氮氧化物还原率的主要决定因素。为了氧化还原成像的目的，3CP被证明是基于可实现的浓度和在体内观察到的生物还原的最佳选择。发现另一个五元环氮氧自由基（指定为23 c）在脑中提供T1对比，表明氮氧自由基穿透血脑屏障。药代动力学研究表明，23 c是一种有效的氧化还原显像剂，在小鼠大脑中，23 c可能允许心肌功能成像以及。23 C可用于评估辐射诱导的神经认知损伤和对脑的其它损伤（包括缺血再灌注损伤）的研究。这种氮氧还被发现是一种非常有效的保护剂，可以防止正常组织（小鼠）的辐射损伤。由于氮氧自由基很容易穿透细胞膜，是有效的抗氧化剂，它们可以用于医学研究的其他领域，如缺血再灌注损伤研究，中风，预防白内障，炎症过程和衰老。基于氮氧化物的MRI评价可能在定义上述病症方面具有临床实用性。