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，进而影响细胞外pH和跨膜pH梯度。现在可以在小动物中商购的电子顺磁共振成像设备可以在没有背景干扰的情况下以3D格式提供有关PO2或pH的特定信息，因为检测到这些参数的顺磁性探针对生物系统是外来的。在这个项目中，将合成一个名为PHMT的三级自由基探针作为双pH-PO2 EPR成像探针在体内。与稳定性和EPR成像分辨率相比，与市售的氮氧化探针相比，TrityL探针具有巨大的优势。高度需要使用双功能Trityl探针对pH和PO2进行体内的EPR成像，因为它将直接证明这两个重要的生物标志物之间的相互作用，但目前不可能在体内。基于我们对芬兰三能型（FT）自旋探针和衍生物的初步数据，提出了一种系统的方法，用于有效合成，并对新的高度水溶性双功能PH-PO2旋转探针进行化学评估，PHMT。我们使用从类似FT化合物获得的数据进行的评估是，PHMT非常适合体内EPR成像应用。该项目将分为 两个部分：SA1：合成PHMT，一种基于羟甲基三元结构的双函数pH-PO2敏感的EPR成像探针。 SA2：通过EPR光谱和成像新合成的探针的特征。