Improved Spin Probes for Magnetic Resonance Imaging of Oxygen and Reactive Oxygen

用于氧气和活性氧磁共振成像的改进自旋探针

• 批准号: 7489920
• 负责人: Laura L Dugan
• 金额: $ 15.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7489920
• 关键词: 12-doxylstearic acid; Acids; Aging-Related Process; Alzheimer' s Disease; Animal Model; Animals; Bioavailable; Biological; Biological Assay; Calibration; Carbon; Cardiac; Cells; Cerebral Ischemia; Characteristics; Chemicals; Chromatography; Class; Cleaved cell; Collaborations; Condition; Coupling; Deposition; Detection; Development; Diabetes Mellitus; Diagnosis; Disadvantaged; Disease; Disease model; Drug or chemical Tissue Distribution; Early Diagnosis; Electron Spin Resonance Spectroscopy; Electrons; Encapsulated; Environment; Esters; Film; Free Radicals; Fullerenes; Functional Magnetic Resonance Imaging; Functional disorder; Gases; Generations; Goals; Heart; High Pressure Liquid Chromatography; Hydroxyl Radical; Image; Imaging Techniques; Ions; Kinetics; Lipids; Location; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measurable; Measurement; Measures; Mediating; Membrane Fluidity; Methods; Micelles; Minor; Mitochondria; Modality; Modification; Molecular; Molecular Probes; Mus; Nature; Nitrogen; Noise; Numbers; Organic solvent product; Oxygen; Oxygen saturation measurement; Parkinson Disease; Parkinson' s Dementia; Particulate; Pathologic; Patients; Penetration; Physiologic pulse; Play; Procedures; Production; Property; Pulse taking; Radiology Specialty; Range; Rattus; Reaction; Reactive Oxygen Species; Reporting; Resolution; Role; Sampling; Shapes; Signal Transduction; Solutions; Source; Spin Trapping; Superoxides; Surface; System; Techniques; Technology; Teflon; Temperature; Time; Tissues; Toluene; Vacuum; Water; Width; age related; animal tissue; aqueous; base; design; effusion; fullerene C60; functional group; fundamental research; human disease; implantation; improved; in vivo; lithium phthalocyanine; novel; novel strategies; professor; research study; response; tissue oxygenation; uptake

DESCRIPTION (provided by applicant): There is currently a need for improved spin probes to help with the diagnosis of and fundamental research into diseases mediated by reactive oxygen species (ROS). This is especially true for the study of age related diseases, since oxidative damage accumulates during the aging process, and many age related disorders such as Parkinson's and Alzheimer's disease are characterized by damage from excess ROS. Spin probes allow these unstable oxygen species to be detected and identified using various magnetic resonance techniques, such as electron paramagnetic resonance (EPR). While certain cancers in animals (Mikuni et al., 2004) and tissues, such as an isolated rat heart (Zweier et al., 1998), have been successfully imaged using EPR imaging, (EPRI), with the current generation of spin probes it is not possible to detect the generation of ROS in age related disorders. The development of new spin probes that allow in vivo detection of ROS produced by Parkinson's and other ROS diseases would represent a significant advance for diagnosing these conditions and for guiding their treatment. To overcome limitations of currently available spin probes, we propose to investigate spin probes based upon single paramagnetic nitrogen atoms encapsulated in C60 fullerenes, N@C60. In this species, the nitrogen is pinned at the center of the symmetric fullerene cage where its unpaired spins are completely protected from reaction with external species. Isolation from the outside environment in the fullerene cage endows N@C60 with one of the narrowest known EPR line widths, (Morton et al., 2006), giving it detection efficiency 100 to 1000 times better than the current spin probes. In addition, interactions with ROS occurring on the surface N@C60 will produce measurable shifts in the spectrum without direct reaction with the probe. These combined features make N@C60 a potentially ideal spin probe. Given the potential of this class of compounds as spin probes and the number of applications that would benefit from such compounds, the overall goal of this project is to synthesize a water-soluble, bioavailable N@C60 derivative, N@C3, and characterize its ability to measure molecular oxygen and biologically important ROS including superoxide using magnetic resonance techniques in vivo. The specific aims of this project are: 1) show that our N@C60 derivative has an EPR signal that is suitable for use as a spin probe for both oximetry and ROS detection, 2) compare N@C3 with currently available spin probes for both oximetry and detection of superoxide and other ROS in aqueous and lipid environments, in cells, and in isolated mitochondria, and 3) Use the technique of Overhauser-enhanced MRI to study the ability of the spin probe to a) enhance spatial resolution of the MRI image, b) substantially improve oxygen mapping by MRI, and c) detect and map ROS in vivo. The proposed studies are the first steps in developing endohedral fullerene-based compounds as novel spin probes, and may open up new avenues for the diagnosis and treatment of diseases ranging from cancer to Alzheimer's. There is growing evidence that reactive oxygen species (ROS) may contribute to the development of many human diseases, including cancer, diabetes, Alzheimer's dementia and Parkinson's disease, but there are currently no techniques which allow ROS (or free radicals) to be measured in patients or in intact animal models of human disease. This project is designed to develop a novel class of "spin probes", molecular agents which are able to interact with ROS to produce a signal which can be detected using various magnetic resonance imaging techniques, such as magnetic resonance imaging (MRI), to assist in early diagnosis and treatment of a broad range of human diseases.

描述（由申请人提供）：目前需要改进的自旋探针来帮助诊断活性氧（ROS）介导的疾病并进行基础研究。对于年龄相关疾病的研究尤其如此，因为氧化损伤在衰老过程中不断积累，许多与年龄相关的疾病，如帕金森病和阿尔茨海默病，其特征是过量活性氧造成的损伤。自旋探针允许使用各种磁共振技术（例如电子顺磁共振（EPR））来检测和识别这些不稳定的氧物质。虽然动物（Mikuni 等人，2004）和组织中的某些癌症（例如离体大鼠心脏（Zweier 等人，1998））已使用 EPR 成像 (EPRI) 和最新一代的自旋探针成功成像在年龄相关疾病中不可能检测到 ROS 的产生。新型自旋探针的开发能够体内检测帕金森氏症和其他 ROS 疾病产生的 ROS，这将代表着诊断这些疾病和指导其治疗的重大进步。为了克服目前可用的自旋探针的局限性，我们建议研究基于封装在 C60 富勒烯 N@C60 中的单个顺磁氮原子的自旋探针。在该物种中，氮被固定在对称富勒烯笼的中心，其不成对的自旋完全受到保护，免于与外部物种发生反应。富勒烯笼中与外部环境的隔离赋予 N@C60 已知最窄的 EPR 线宽之一（Morton 等人，2006），使其检测效率比当前的自旋探针高 100 至 1000 倍。此外，N@C60 表面上发生的与 ROS 的相互作用将在光谱中产生可测量的变化，而无需与探针直接反应。这些综合功能使 N@C60 成为潜在的理想自旋探针。鉴于此类化合物作为自旋探针的潜力以及受益于此类化合物的应用数量，该项目的总体目标是合成水溶性、生物可利用的 N@C60 衍生物 N@C3，并表征其能够使用体内磁共振技术测量分子氧和生物学上重要的活性氧（包括超氧化物）。该项目的具体目标是：1) 表明我们的 N@C60 衍生物具有 EPR 信号，适合用作血氧测定和 ROS 检测的自旋探针，2) 将 N@C3 与当前可用的自旋探针进行比较血氧测定法以及水和脂质环境、细胞和分离线粒体中超氧化物和其他 ROS 的检测，以及 3) 使用 Overhauser 增强 MRI 技术来研究自旋探针 a) 增强空间分辨率的能力MRI 图像的分析，b) 通过 MRI 显着改善氧分布图，c) 检测并绘制体内 ROS 分布图。拟议的研究是开发基于内嵌富勒烯的化合物作为新型自旋探针的第一步，并可能为从癌症到阿尔茨海默氏症等疾病的诊断和治疗开辟新途径。越来越多的证据表明，活性氧 (ROS) 可能会导致许多人类疾病的发生，包括癌症、糖尿病、阿尔茨海默氏痴呆和帕金森病，但目前还没有技术可以在体内测量 ROS（或自由基）。患者或人类疾病的完整动物模型。该项目旨在开发一类新型“自旋探针”，即能够与 ROS 相互作用产生信号的分子制剂，该信号可以使用各种磁共振成像技术（例如磁共振成像 (MRI)）检测到，以协助广泛的人类疾病的早期诊断和治疗。