Macrophage elastase and its imaging in vascular inflammation and remodeling

描述(申请人提供)：血管疾病仍然是世界上发病率和死亡率的主要原因。可利用非侵入性成像手段检测与血管并发症有关并增加血管并发症风险的血管壁炎和重塑等特征，有助于降低这种发病率和死亡率。传统的血管成像方法中存在的主要缺陷可以通过检测体内相关靶点的分子成像来解决。为此，具有广泛特异性的基质金属蛋白酶(MMPs)示踪剂已经被开发出来，并用于检测体内的血管重构和炎症。尽管这些广泛特异的药物有望成为一线药物，但它们在血管重塑和炎症的发病机制中受到不同的、有时甚至是相反的基质金属蛋白酶家族成员的作用的限制。巨噬细胞弹性蛋白酶(MMP12)在动脉粥样硬化和动脉瘤的发生发展中起关键作用。RXP470是一种选择性且有效的基质金属蛋白酶-12抑制剂，可抑制动脉粥样硬化斑块的发展，并促进稳定的斑块表型。在这里，我们假设动脉粥样硬化和动脉瘤中的血管壁炎症和重塑可以通过体内激活的基质金属蛋白酶-12的分子成像来检测。我们的具体目标是开发和验证用于分子成像的新型基质金属蛋白酶-12靶向示踪剂，并验证基质金属蛋白酶-12的活性形式作为巨噬细胞激活的标志和动脉瘤和动脉粥样硬化中血管炎症和重塑的成像靶点。基于RXP470的结构，我们已经开发并初步测试了用于分子成像的新型荧光和放射性标记探针。在这里，这一示踪剂组合将针对分子成像进行扩展和优化。激活的基质金属蛋白酶-12作为炎症和血管细胞激活和分化的标志的有效性将被讨论。最后，将使用互补的小鼠动脉瘤和动脉粥样硬化模型来验证基质金属蛋白酶-12靶向成像通过体外荧光成像和体内SPECT成像检测血管壁炎症和重塑。如果得到验证，基质金属蛋白酶-12靶向成像可以识别有急性冠脉综合征和动脉瘤破裂风险的患者，并帮助跟踪血管疾病新的治疗干预措施的效果。

DESCRIPTION (provided by applicant): Vascular diseases remain major causes of morbidity and mortality in the world. The availability of noninvasive imaging modalities for detection of features such as vessel wall inflammation and remodeling that are involved in, and increase the risk of vascular complications can help reduce this morbidity and mortality. Major existing gaps in the traditional approach to vascular imaging may be addressed by molecular imaging aimed at detecting relevant targets in vivo. To this means, tracers with broad specificity for matrix metalloproteinases (MMPs) have been developed and used to detect vascular remodeling and inflammation in vivo. While promising as first line agents, the effectiveness of these broadly specific agents is limited by diverse and at times opposing effects of different members of the MMP family in the pathogenesis of vascular remodeling and inflammation. Macrophage elastase (MMP-12) plays a key role in the development of atherosclerosis and aneurysm. RXP470, a selective and potent inhibitor of MMP-12, inhibits atherosclerotic plaque development and promotes a stable plaque phenotype. Here, we hypothesize that vessel wall inflammation and remodeling in atherosclerosis and aneurysm can be detected by molecular imaging of activated MMP-12 in vivo. Our specific aims are to develop and validate novel MMP-12-targeted tracers for molecular imaging and to validate the active form of MMP-12 as a marker of macrophage activation and target for imaging of vascular inflammation and remodeling in aneurysm and atherosclerosis. Based on the structure of RXP470 we have developed and preliminarily tested novel fluorescent and radiolabeled probes for molecular imaging. Here, this portfolio of tracers will be expanded and optimized for molecular imaging. The effectiveness of activated MMP-12 as a marker of inflammatory and vascular cell activation and differentiation will be addressed. Finally, complementary murine models of aneurysm and atherosclerosis will be used to validate MMP-12-targeted imaging for detection of vessel wall inflammation and remodeling by fluorescent imaging ex vivo and SPECT imaging in vivo. If validated, MMP-12 targeted imaging may identify patients at risk for acute coronary syndromes and aneurysm rupture and help track the effect of novel therapeutic interventions in vascular diseases.