Macrophage elastase and its imaging in vascular inflammation and remodeling

描述（由申请人提供）：血管疾病仍然是世界上发病和死亡的主要原因。使用无创成像方式检测血管壁炎症和重塑等特征并增加血管并发症的风险，有助于降低发病率和死亡率。传统血管成像方法中存在的主要差距可以通过旨在检测体内相关目标的分子成像来解决。这意味着，已经开发出对基质金属蛋白酶（MMP）具有广泛特异性的示踪剂，并用于检测体内血管重塑和炎症。虽然作为一线药物很有希望，但这些广泛特异性药物的有效性受到 MMP 家族不同成员在血管重塑和炎症发病机制中的不同且有时相反的影响的限制。巨噬细胞弹性蛋白酶（MMP-12）在动脉粥样硬化和动脉瘤的发展中发挥着关键作用。 RXP470 是一种选择性且有效的 MMP-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 MMP-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 MMP-12 靶向示踪剂，并验证 MMP-12 的活性形式作为巨噬细胞活化的标记物以及血管炎症成像和动脉瘤和动脉粥样硬化重塑的靶标。基于RXP470的结构，我们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，该示踪剂组合将针对分子成像进行扩展和优化。将讨论活化的 MMP-12 作为炎症和血管细胞活化和分化标志物的有效性。 最后，动脉瘤和动脉粥样硬化的互补小鼠模型将用于验证 MMP-12 靶向成像，用于通过离体荧光成像和体内 SPECT 成像检测血管壁炎症和重塑。如果经过验证，MMP-12 靶向成像可以识别有急性冠状动脉综合征和动脉瘤破裂风险的患者，并帮助追踪血管疾病的新型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.