转运蛋白特异性配体用于动脉粥样硬化易损斑块的PET显像研究

动脉粥样硬化易损斑块的破裂是导致急性心肌梗死的重要原因，但目前对斑块的不稳定性评价仍然缺乏有效的无创功能显像方法。研究发现激活的巨噬细胞内线粒体上大量表达外周型苯二氮卓受体转运蛋白（TSPO），斑块纤维帽内激活的巨噬细胞含量和其炎症反应程度存在着正相关性，巨噬细胞越多，斑块不稳定性越高。另外，我们前期研究也表明凋亡的巨噬细胞可以作为核医学显像斑块的靶点。提示：正电子核素标记TSPO配体，有望应用于动脉粥样硬化斑块不稳定性的正电子发射断层扫描（PET）显像。本项目将设计合成一种高亲和力、受体结合动力学及体内药代动力学相匹配的I-124标记TSPO配体，并将其在ApoE-/-小鼠的显像结果与TSPO经典显像剂C-11-PK11195相互比较，为斑块定位及其不稳定性判断提供一种无创的功能显像手段。

Vulnerable atherosclerosis(AS) plaque rupture is the main cause of acute myocardial infarction (AMI), but so far there is still lacking effective non-invasive functional imaging method for vulnerability evaluation of atherosclerosis plaques. Previous research indicated that a lot of translocator protein (TSPO) expressed on the outer membrane of mitochondria inside macrophages, and a large number of pro-inflammatory activated macrophages existing within thin fibrous cap of vulnerable plaque. There is a positive correlation between the degree of inflammation and the content of macrophages. More macrophages indicated higher plaque instability. In addition, our previous study also showed that apoptotic macrophages could be served as target for nuclear medicine imaging. These results help to propose that positron isotopes labeled TSPO ligands could be used for positron emission tomography (PET) imaging of vulnerability of plaques. To prove this hypothesis, we aim to design and synthesize an I-124 labeled TSPO ligand, which is expected to possess high affinity, suitable receptor binding kinetics and in vivo pharmacokinetics. Further micro-PET evaluation will be performed in ApoE-/- mice with this probe, and comparing study with C-11-PK11195 as a classic TSPO probe will be conducted as well. It's expected to establish a non-invasive functional imaging method for atherosclerosis plaques localization and their vulnerability evaluation.