Dual function pH and oxygen probes for in vivo EPR spectroscopy and imaging

用于体内 EPR 光谱和成像的双功能 pH 和氧探头

• 批准号: 7686198
• 负责人: Valery V Khramtsov
• 金额: $ 22.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686198
• 关键词: Accounting; Acidic Region; Acidosis; Ascorbic Acid; Biochemical Process; Biological; Biomedical Research; Cells; Characteristics; Chemicals; Development; Electron Spin Resonance Spectroscopy; Future; Goals; Heart; Homeostasis; Image; Imidazole; Injury; Ischemia; Ischemic Preconditioning; Life; Magnetic Resonance; Maps; Measurement; Measures; Medicine; Metabolism; Modeling; Molecular Probes; Myocardial; Myocardial Ischemia; Oxygen; Oxygen saturation measurement; Physiological; Play; Procedures; Rattus; Reducing Agents; Reporting; Resolution; Role; Route; Sampling; Solubility; Structure; Superoxides; Testing; Therapeutic; Tissues; base; bioimaging; design; in vivo; lipophilicity; nitroxyl; preconditioning; spectroscopic imaging; success; tool

DESCRIPTION (provided by applicant): The overall goal of this project is to develop new probes of enhanced functionality and stability for in vivo EPR spectroscopy and imaging. Functionally oriented classes of soluble paramagnetic probes such as pH, SH- and NO-sensitive nitroxyl radicals (NR) have been developed but they often suffer from insufficient stability in living tissues. In turn, triarylmethyl (TAM) radicals have been the popular choice for EPR imaging applications offering advantages over nitroxides, that is, stability in cells and tissues, and narrow linewidth, resulting in high analytical resolution at 5M concentrations and enhanced sensitivity to O2. However, until now applications of TAM radicals have been functionally limited, mostly to EPR oximetry. In this project we propose to enhance the functionality of TAM radicals by developing pH sensitive derivatives in addition to oxygen sensing. Taking into account that both oxygen and pH play key roles in cellular metabolism and homeostasis, these probes may become useful tools in biomedical research. The specific aims are: (SA1) to synthesize pH-sensitive trityl radicals. The synthetic route for the incorporation of specific ionizable groups, which provide pH sensitivity to TAM derivatives in the desirable pH range, is proposed. The probes synthesized under the SA1 are the basis for the entire project. (SA2) To define the spectroscopic and physico-chemical characteristics of pH- and O2-sensitive TAMs. Quantitative characterization of the newly synthesized TAMs is absolutely crucial, both for the optimization of the synthetic procedure (i.e. the choice of the most effective probes) and for the efficiency of their further spectroscopic and imaging applications. (SA3) To study the role of myocardial acidosis and oxygen depletion in ischemic hearts and in the model of ischemic preconditioning using newly developed TAMs. The measurement of pH and oxygen depletion in ischemic heart is of principal importance for understanding related biochemical processes believed to contribute to myocardial injury, and will be measured in controlled and preconditioned rat hearts using developed extremely stable probes of dual functionality. The results will contribute to the understanding of preconditioning mechanisms and provide opportunities for designing corresponding therapeutic approaches. In summary, the success of this project may have a significant impact on the future of in vivo EPR spectroscopy and bioimaging applications to medicine.

描述(由申请人提供)：该项目的总体目标是开发新的探针，增强功能和稳定性，用于体内EPR波谱和成像。功能导向类的可溶性顺磁探针，如pH、SH-和不敏感的硝基自由基(NR)已被开发出来，但它们在活体组织中往往存在稳定性不足的问题。反过来，三芳甲基()自由基一直是电子顺磁共振成像应用的热门选择，与氮氧化物相比具有优势，即在细胞和组织中的稳定性，以及窄的线宽，导致在5M浓度下的高分析分辨率和对O2的增强敏感性。然而，到目前为止，自由基的应用一直受到功能上的限制，主要是在EPR血氧法方面。在这个项目中，我们建议通过开发pH敏感的衍生物来增强自由基的功能，而不是氧气传感。考虑到氧和pH在细胞代谢和动态平衡中都起着关键作用，这些探针可能成为生物医学研究中有用的工具。其具体目标是：(SA1)合成pH敏感的三叔丁基自由基。提出了在合适的pH范围内对衍生物具有pH敏感性的特殊可电离基团的合成路线。在SA1下合成的探针是整个项目的基础。(SA2)确定对pH和O2敏感的TAMs的光谱和物理化学特性。新合成的TAMS的定量表征对于合成过程的优化(即选择最有效的探针)以及它们进一步的光谱和成像应用的效率都是绝对关键的。(SA3)用新开发的TAMS研究心肌酸中毒和缺氧在缺血心脏和缺血预适应模型中的作用。测量缺血心脏的pH值和氧耗量对于了解导致心肌损伤的相关生化过程是非常重要的，并将使用开发的极其稳定的双功能探针在受控和预适应的大鼠心脏中进行测量。这一结果将有助于理解预适应机制，并为设计相应的治疗方法提供机会。综上所述，该项目的成功可能会对活体EPR波谱和生物成像在医学上的应用产生重大影响。