Synthesis of a dual pH-pO2 hydromethyl trityl probe for EPR imaging in vivo

用于体内 EPR 成像的双 pH-pO2 氢甲基三苯甲基探针的合成

• 批准号: 8493034
• 负责人: Ilirian Dhimitruka
• 金额: $ 7.66万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493034
• 关键词: Acid-Base Equilibrium; Acidity; Animal Model; Animals; Biological; Biological Markers; Blood capillaries; Cells; Data; Electron Spin Resonance Spectroscopy; Environment; Equipment; Evaluation; Finland; Healthcare; Heterogeneity; Hybrids; Hypoxia; Image; Imaging Phantoms; Imaging Techniques; In Vitro; Injury; Knowledge; Lipid Bilayers; Literature; Magnetic Resonance Imaging; Malignant Neoplasms; Maps; Measures; Metabolism; Monitor; Names; Oxygen; Physiological; Plasma; Procedures; Process; Radiation therapy; Reporting; Research; Resistance; Resolution; Sampling; Signal Transduction; Simulate; Solid Neoplasm; Structure; Therapeutic; Tissues; Training; Trityl Compounds; Tube; Vascular blood supply; Water; angiogenesis; ascorbate; base; bioimaging; biological systems; capillary; chemical synthesis; chemotherapy; clinical application; experience; extracellular; hydroxyl group; imaging probe; improved; in vivo; instrument; metastatic process; neoplastic cell; pH gradient; public health relevance; ratiometric; tissue oxygenation; tumor; tumor progression

DESCRIPTION (provided by applicant): The noninvasive imaging of tissue oxygenation and acidity is of utmost importance in evaluating tumor progression, or ischemic injury, and selection of appropriate therapies. Cell metabolism depends on the oxygen supply, which in turn influences the extracellular pH, and transmembrane pH gradients. Electron Paramagnetic Resonance Imaging equipment, which is now commercially available for use in small animals, can provide specific information about pO2 or pH in 3D format without background interference, because paramagnetic probes that detect these parameters are exogenous to biological systems. In this project, a trityl radical probe named pHMT will be synthesized for use as dual pH-pO2 EPR Imaging probe in vivo. Trityl probes offer enormous advantages compared to the commercially available nitroxide probes in terms of stability, and EPR imaging resolution. Concurrent EPR imaging of pH and pO2 in vivo using dual-function trityl probes is highly desired, as it will provide direct evidence of the interplay between these two important biomarkers, but for the moment it is not possible in vivo. Based on our preliminary data on Finland trityl (FT) spin probes and derivatives, a systematic approach is proposed for the efficient synthesis, and chemical evaluation of a new, highly water soluble dual function pH-pO2 spin probe, pHMT. Our assessment formulated with data obtained from similar FT compounds is that pHMT is ideally suited for EPR imaging applications in vivo. The project will be divided in two parts: SA1: Synthesize pHMT, a dual function pH-pO2 sensitive EPR imaging probe based on hydroxymethyl trityl structure. SA2: Characterize via EPR spectroscopy and imaging the newly synthesized probes.

描述（由申请人提供）：组织氧合和酸度的无创成像对于评估肿瘤进展或缺血性损伤以及选择适当的疗法至关重要。细胞代谢取决于氧气供应，这反过来又影响细胞外 pH 值和跨膜 pH 梯度。电子顺磁共振成像设备现已商业化用于小动物，可以以 3D 格式提供有关 pO2 或 pH 的特定信息，而不会产生背景干扰，因为检测这些参数的顺磁探针对于生物系统来说是外源性的。在该项目中，将合成一种名为pHMT的三苯甲基自由基探针，用作体内双pH-pO2 EPR成像探针。与市售硝基氧探针相比，三苯甲基探针在稳定性和 EPR 成像分辨率方面具有巨大优势。非常需要使用双功能三苯甲基探针对体内 pH 和 pO2 进行同步 EPR 成像，因为它将提供这两个重要生物标志物之间相互作用的直接证据，但目前在体内还不可能。基于我们对芬兰三苯甲基 (FT) 自旋探针和衍生物的初步数据，提出了一种系统方法，用于高效合成和化学评估新型高水溶性双功能 pH-pO2 自旋探针 pHMT。我们根据类似 FT 化合物获得的数据进行评估，认为 pHMT 非常适合体内 EPR 成像应用。该项目将分为 两部分： SA1：合成pHMT，一种基于羟甲基三苯甲基结构的双功能pH-pO2敏感EPR成像探针。 SA2：通过 EPR 光谱表征并对新合成的探针进行成像。