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

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治疗方法至关重要。细胞代谢依赖于氧供应，而氧供应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，现在已经商业化，可用于小动物，可以在没有背景干扰的情况下以3D格式提供关于pO2或pH的特定信息，因为检测这些参数的顺磁探针对生物系统是外生的。本项目将合成一种名为pHMT的三烷基自由基探针，用于体内双pH-pO2 EPR成像探针。与市售的氮氧化物探针相比，三烷基探针在稳定性和EPR成像分辨率方面具有巨大的优势。使用双功能三烷基探针同时进行体内pH和pO2的EPR成像是非常需要的，因为它将提供这两种重要生物标志物之间相互作用的直接证据，但目前在体内是不可能的。基于芬兰三烷基（FT）自旋探针及其衍生物的初步研究数据，本文提出了一种高效合成和化学评价新型高水溶性双功能pH-pO2自旋探针pHMT的系统方法。我们根据从类似FT化合物中获得的数据得出的评估是，pHMT非常适合体内EPR成像应用。这个项目将被分成几个部分

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.