METABOLIC IMAGING AGENTS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 具体目标是：1）优化我们现有的葡萄糖响应性PARACEST试剂，用于绘制体内葡萄糖的组织分布。我们已经证明，细胞外葡萄糖浓度的变化，可以映射通过MRI在离体小鼠肝脏CEST成像使用葡萄糖响应PARACEST剂。这假设硼酸盐试剂均匀分布在肝脏的所有细胞外空间中。设想进一步的实验来检验这一假设。2)开发一种通过MRI标测组织pH值的单次注射方法。我们首先证明，通过在注射两种试剂（pH不敏感剂（GdDOTp 5-）和pH敏感剂（GdDOTA-4Amp 5-））后监测动态对比增强（DCE），可以通过MRI在体内绘制肾脏、心脏和肿瘤中的组织pH。为了使组织的pH成像在临床上更加可行，我们建议开发一种使用T1和T2试剂混合物的单次注射方案。3)开发用于组织的低pH区域成像的高灵敏度LlPOCEST颗粒。已经证明，CEST的灵敏度可以放大许多倍，通过使用脂质体包含高浓度的镧系元素位移试剂捕获在内核中。与复合物沿着被捕获在内核中的所有水被转移到与脂质体外水不同的频率，并且这种新的共振可以用作启动CEST的天线。由于在这种情况下，水的交换是由脂质双层的扩散特性决定的，因此应该能够制备具有响应脂质体外pH变化的表面官能团的脂质体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specific aims are to: 1) Optimize our existing glucose-responsive PARACEST agent for mapping the tissue distribution of glucose in vivo. We have demonstrated that changes in extracellular glucose concentration can be mapped by MRI in isolated mouse liver by CEST imaging using a glucose-responsive PARACEST agent. This assumes that the boronate agent is equally distributed throughout all extracellular space of liver. Further experiments are envisioned to test this hypothesis. 2) Develop a single injection method for mapping tissue pH by MRI. We were first to demonstrate that tissue pH can be mapped by MRI in kidney, heart & tumors in vivo by monitoring dynamic contrast enhancement (DCE) after injection of two agents, a pH insensitive agent (GdDOTp5-) and a pH sensitive agent (GdDOTA-4Amp5-). In an effort to make pH imaging of tissue more feasible clinically, we propose to develop a single injection protocol using a mixture T1 and T2 agents. 3) Develop high sensitivity LlPOCEST particles for imaging low pH regions of tissues. It has been demonstrated that the sensitivity of CEST can be magnified many fold by using liposomes containing high concentrations of lanthanide shift reagent trapped in the inner core. All water trapped in the inner core along with a complex is shifted to a different frequency than extra-liposomal water and this new resonance can be used as an antenna to initiate CEST. Since exchange of water in this case is determined by the diffusion characteristics of the lipid bilayer, one should be able to prepare liposomes with surface functionalities that respond to changes in extraliposomal pH.