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

描述(由申请人提供)：组织氧合和酸度的非侵入性成像在评估肿瘤进展或缺血性损伤以及选择适当的治疗方法方面至关重要。细胞的新陈代谢依赖于氧气供应，而氧气供应反过来又影响细胞外的pH，以及跨膜的pH梯度。电子顺磁共振成像设备现在可以在商业上用于小动物，它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测器是生物系统的外源性。在本项目中，将合成一种名为PHMT的三苯基自由基探针，用于体内的双pH-PO2EPR成像探针。与商用的氮氧化物探针相比，Trityl探针在稳定性和EPR成像分辨率方面具有巨大的优势。使用双功能三叔丁基探针同时进行体内pH和PO2的EPR成像是非常必要的，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，但目前还不可能在体内进行。基于我们关于芬兰三苯基(FT)自旋探针及其衍生物的初步数据，提出了一种新的、高度水溶性的双功能pH-PO2自旋探针PHMT的有效合成和化学评价的系统方法。我们从类似FT化合物获得的数据得出的评估是，PHMT非常适合体内EPR成像应用。该项目将被分成 两部分：SA1：合成了一种基于羟甲基三苯基结构的双功能pH-PO2敏感EPR成像探针。SA2：通过EPR波谱对新合成的探针进行表征和成像。

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.