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治疗方面至关重要。细胞代谢取决于氧供应，这反过来又影响细胞外pH和跨膜pH梯度。电子顺磁共振成像设备，这是现在商业上可用于小动物，可以提供特定的信息pO 2或pH值的3D格式没有背景干扰，因为顺磁探针检测这些参数是外源性的生物系统。本课题拟合成一种三苯甲基自由基探针pHMT，作为pH-pO 2双探针，用于体内EPR成像。与市售氮氧化合物探针相比，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。使用双功能三苯甲基探针在体内同时进行pH和pO 2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，但目前还不可能在体内进行。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，提出了一种系统的方法，有效的合成，和化学评价的一种新的，高水溶性的双功能pH-pO 2自旋探针，pHMT。我们的评估制定从类似的FT化合物获得的数据是，pHMT是理想的EPR成像应用在体内。该项目将分为 SA 1：合成一种基于羟甲基三苯甲基结构的pH-pO_2双功能EPR成像探针pHMT。SA 2：通过EPR光谱和成像新合成的探针进行表征。

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.