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: 7532450
• 负责人: Valery V Khramtsov
• 金额: $ 18.75万
• 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/7532450
• 关键词: Accounting; Acidic Region; Acidosis; Ascorbic Acid; Biochemical Process; Biological; Biomedical Research; Cells; Characteristics; Chemicals; Class; 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; Range; 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具有增强功能和稳定性的新型探针，用于体内EPR光谱和成像。功能导向的可溶性顺磁探针如pH、SH和no敏感的硝基自由基（NR）已经被开发出来，但它们在活组织中往往缺乏稳定性。反过来，三芳基甲基（TAM）自由基一直是EPR成像应用的热门选择，它比氮氧化物具有优势，即在细胞和组织中具有稳定性，线宽窄，在5M浓度下具有高分析分辨率，并增强了对O2的敏感性。然而，到目前为止，TAM自由基的应用功能有限，主要用于EPR氧饱和度测定。在这个项目中，我们建议通过开发pH敏感衍生物来增强TAM自由基的功能。考虑到氧和pH值在细胞代谢和体内平衡中都起着关键作用，这些探针可能成为生物医学研究的有用工具。具体目的是：（SA1）合成ph敏感的三烷基自由基。提出了加入特定电离基团的合成路线，在理想的pH范围内对TAM衍生物提供pH敏感性。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tam的光谱和物理化学特性。新合成的tam的定量表征对于合成过程的优化（即选择最有效的探针）以及其进一步的光谱和成像应用的效率都是至关重要的。（SA3）利用新研制的TAMs研究心肌酸中毒和缺氧在缺血心脏及缺血预处理模型中的作用。测量缺血心脏的pH值和氧消耗对于理解导致心肌损伤的相关生化过程至关重要，并且将使用开发的非常稳定的双功能探针在受控和预处理大鼠心脏中进行测量。这些结果将有助于理解预处理机制，并为设计相应的治疗方法提供机会。综上所述，该项目的成功可能对体内EPR光谱和生物成像在医学上的应用产生重大影响。