Development of Improved Spin Probes for Aging Research

用于老化研究的改进自旋探针的开发

• 批准号: 7219781
• 负责人: JOHN M ALFORD
• 金额: $ 18.38万
• 依托单位: TDA RESEARCH, INC.
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219781
• 关键词: 12-doxylstearic acid; Aging; Aging-Related Process; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Area; Biological; Biological Assay; Blood - brain barrier anatomy; Calibration; Carboxylic Acids; Cell membrane; Cells; Characteristics; Chromatography; Cleaved cell; Condition; Data; Deposition; Detection; Development; Diagnosis; Disadvantaged; Disease; Drug Kinetics; Electron Spin Resonance Spectroscopy; Electrons; Encapsulated; Environment; Esters; Evaluation; Extinction (Psychology); Extravasation; Film; Fullerenes; Gases; Generations; Government; Half-Life; Heart; High Pressure Liquid Chromatography; Hydroxylamine; Image; Imaging Techniques; Imaging technology; Ions; Life; Localized; Location; Magnetic Resonance; Malignant Neoplasms; Measurable; Measurement; Measures; Mediating; Metabolism; Methods; Mitochondria; Molecular; Molecular Probes; Monitor; Mus; Nature; Nitrogen; Noise; Object Attachment; Organ; Organic solvent product; Oxygen; Oxygen saturation measurement; Parkinson Disease; Particulate; Persons; Phase; Procedures; Property; Purpose; Rattus; Reaction; Reactive Oxygen Species; Reporting; Research; Sampling; Series; Signal Transduction; Small Business Technology Transfer Research; Solutions; Superoxides; Surface; System; Techniques; Teflon; Temperature; Testing; Time; Tissues; Toluene; Trityl Compounds; Tube; Vacuum; Water; Width; Work; Xanthine Oxidase; adduct; age related; analog; animal tissue; aqueous; base; design; desire; effusion; fullerene C60; functional group; fundamental research; implantation; improved; in vivo; interest; lithium phthalocyanine; research study

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 current spin probe compounds, 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 a detection efficiency 100 to 1000 times better than the current compounds. Reactions of ROS occurring on the surface N@C60 will produce measurable shifts in the spectrum. These combined features make N@C60 the ideal spin probe. Given its high potential to make a nearly perfect spin probe, the aim of this project is to synthesize and characterize a spin probe based on N@C60 for molecular oxygen, superoxide, and other biologically important reactive oxygen species. The specific aims of this phase I project are: 1) First establish that it is possible to produce our candidate spin probe in quantities sufficient for testing, 2) Show that our N@C60 derivative has an EPR signal suitable for use as a spin probe, and 3) Provide preliminary data for comparison with currently available spin probes, including the detection of superoxide. Many age related disorders such as Parkinson's and Alzheimer's disease are characterized by damage from excess reactive oxygen species (ROS), and it is not possible with the current imaging technology to non-invasively detect the generation of ROS in people. Spin probes are molecular agents designed to react with reactive oxygen species (ROS) which enables them to be detected and identified using various magnetic resonance techniques. To overcome the limitations of current agents and enable the development of better imaging techniques for ROS disorders, we propose to investigate new types of spin probes based upon paramagnetic nitrogen atoms encapsulated in C60 fullerenes, N@C60. 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.

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。为了克服当前自旋探针化合物的局限性，我们建议研究基于封装在 C60 富勒烯 N@C60 中的单个顺磁性氮原子的自旋探针。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），使其检测效率比现有化合物高 100 至 1000 倍。 N@C60 表面发生的 ROS 反应将产生可测量的光谱变化。这些综合功能使 N@C60 成为理想的自旋探针。鉴于其制造近乎完美的自旋探针的巨大潜力，该项目的目标是合成和表征基于 N@C60 的自旋探针，用于分子氧、超氧化物和其他生物学上重要的活性氧。该第一阶段项目的具体目标是：1）首先确定可以生产足够数量的候选自旋探针以供测试，2）表明我们的 N@C60 衍生物具有适合用作自旋探针的 EPR 信号，以及 3) 提供与当前可用的自旋探针进行比较的初步数据，包括超氧化物的检测。 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（ROS）造成的损害，目前的成像技术不可能无创地检测人体内ROS的产生。自旋探针是一种分子试剂，旨在与活性氧 (ROS) 发生反应，从而可以使用各种磁共振技术来检测和识别它们。为了克服当前试剂的局限性并开发更好的 ROS 疾病成像技术，我们建议研究基于封装在 C60 富勒烯 N@C60 中的顺磁性氮原子的新型自旋探针。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。