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为体内EPR光谱和成像增强功能和稳定性的新探针。已经开发了以功能为导向的可溶性顺磁性探针，例如pH，sh-和无敏感的硝氧基自由基（NR），但它们在活组织中的稳定性通常不足。反过来，三甲基甲基（TAM）自由基一直是EPR成像应用的流行选择，其优势比硝基氧化物，即细胞和组织中的稳定性以及狭窄的线宽，从而在5m的浓度下以5m的浓度和增强的O2敏感性在高度分析中分析。但是，到目前为止，TAM自由基的应用在功能上受到限制，主要用于EPR血氧仪。在这个项目中，我们建议除了氧气传感外，还通过开发pH敏感衍生物来增强TAM自由基的功能。考虑到氧气和pH在细胞代谢和稳态中都起着关键作用，这些探针可能成为生物医学研究中的有用工具。具体目的是：（SA1）合成对pH敏感的三利自由基。提出了掺入特定电离基团的合成途径，这些途径提出了对所需pH范围内TAM衍生物的pH敏感性。 SA1下合成的探针是整个项目的基础。 （SA2）定义pH-和O2敏感TAM的光谱和物理化学特征。新合成的TAM的定量表征对于优化合成程序（即最有效的探测器的选择）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）研究心肌酸中毒和氧耗竭在缺血性心脏以及使用新开发的TAM的缺血性预处理模型中的作用。缺血性心脏中pH和氧耗竭的测量对于理解被认为会导致心肌损伤的相关生物化学过程至关重要，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的大鼠心脏中测量。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。总之，该项目的成功可能会对体内EPR光谱和医学生物成像应用的未来产生重大影响。