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）：目前需要改进自旋探针，以帮助对由活性氧（ROS）介导的疾病的诊断和基本研究。对于对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会累积，许多与年龄相关的疾病（如帕金森氏症和阿尔茨海默氏病）的特征是多余的ROS损害。自旋探针允许使用各种磁共振技术（例如电子顺磁共振（EPR））检测和鉴定这些不稳定的氧。尽管动物中的某些癌症（Mikuni等，2004）和组织（例如孤立的大鼠心脏（Zweier等，1998））已通过EPR成像（EPRI）成功成像，而当前的自旋探针则无法检测到与年龄相关的疾病中的ROS产生。允许在帕金森氏症和其他ROS疾病产生的ROS的新自旋探针的开发将代表诊断这些疾病并指导其治疗的重大进步。为了克服当前可用的自旋探针的局限性，我们建议研究基于C60 Fullerenes中封装的单个顺磁性氮原子，N@C60。在该物种中，将氮固定在对称的富勒烯笼的中心，在该中心，其未配对的旋转完全受到与外部物种反应的反应。从富勒烯笼中的外部环境中分离出N@C60具有最狭窄的EPR线宽度之一（Morton等，2006），使其比当前的自旋探针高100至1000倍。此外，与在表面N@C60上发生的ROS的相互作用将在频谱中产生可测量的移位，而无需直接与探针反应。这些组合功能使N@C60成为潜在理想的自旋探针。考虑到这类化合物作为自旋探针的潜力以及将从此类化合物中受益的应用数量，因此该项目的总体目标是合成水可溶性，生物可生物可利用的N@C60衍生物N@C3，并表征其在包括磁性磁性磁化技术（包括磁性磁氧化剂）中的分子氧气和生物学上重要的Rosogulan氧化物的能力。该项目的具体目的是：1）证明我们的N@C60衍生物具有EPR信号，适用于用作血氧仪和ROS检测的自旋探针，2）将N@C3与当前可用的氧仪和可用的旋转探针进行比较，用于氧化型和在水上和脂质环境中的超级氧化物和其他ROS和其他在近距离和脂质环境中的检测，并在近距离和脂质环境中，以及3个属于MITRIDIRIFIRIDIRIDIRACENT和3的方法。 MRI研究自旋探针对a）增强MRI图像的空间分辨率的能力，b）基本上改善了MRI的氧映射，c）检测并在体内映射ROS。拟议的研究是开发基于富勒烯的内膜化合物作为新型自旋探针的第一步，并可能为诊断和治疗从癌症到阿尔茨海默氏病等疾病的新途径开放。越来越多的证据表明，活性氧（ROS）可能有助于许多人类疾病的发展，包括癌症，糖尿病，阿尔茨海默氏症的痴呆症和帕金森氏病，但目前没有一些允许ROS（或自由基）在患者或完整的人类疾病动物模型中进行测量的技术。该项目旨在开发一种新型的“自旋探针”，即能够与ROS相互作用的分子剂，以产生可以使用各种磁共振成像技术（例如磁共振成像（MRI））检测到的信号，以帮助早期诊断和治疗广泛的人类疾病。