PET Imaging of MMP Activation in AAA: First in-Human Evaluation

摘要 腹主动脉瘤(AAA)每年导致10,000人死亡。 我们。虽然大多数动脉瘤是无症状的，但高度致命的并发症、破裂和夹层确实发生在 患者的子集。动脉瘤直径是预测其破裂倾向的最著名的指标，而且 因此，对于大型或有症状的腹主动脉瘤，建议采用动脉瘤修补术。然而，许多破裂 发生在不符合修复标准的较小的动脉瘤中；反之，一些较大的动脉瘤 切勿破裂。AAA的治疗仍然局限于手术或血管内修复，因为有几种很有希望的医学方法 治疗方法在临床研究中失败了。因此，需要新的工具(例如，分子成像)来提高风险 对患者进行分层，开发有效的医疗疗法，并监测治疗效果。矩阵 金属蛋白酶(MMPs)激活促进AAA血管重塑，部分是通过降解 弹性蛋白和其他基质蛋白。我们之前的研究已经确定了靶向基质金属蛋白酶的可行性 微单光子发射计算机断层扫描(SPECT)/CT成像检测大鼠血管重塑 小鼠动脉瘤模型。然而，SPECT示踪剂和技术的一些限制被排除在外 血管成像的临床翻译。为了解决这些局限性，我们开发了一种新型的基质金属蛋白酶家族-- 具有改进的药代动力学的靶向示踪剂(RYM)，包括第一类正电子发射 断层扫描(PET)示踪剂，64Cu-RYM2。在这里，我们寻求进一步的开发、评估和临床翻译 64Cu-RYM2首次用于AAA的人体成像研究，假设用64Cu-RYM2进行的MMPPET/CT成像 RYM2可检测AAA基质金属蛋白酶活性。我们的具体目标是评估64Cu-RYM2与人AAA的结合 组织；64Cu-RYM2在小鼠AAA中的药代动力学和成像性能与组织的关系 并翻译64Cu-RYM2用于人AAA显像。利用资源和 耶鲁医学院和华盛顿的PI和协查人员的互补专业知识 包括由NIBIB资助的华盛顿大学P41中心，这些研究将建立 64Cu-RYM2在人腹主动脉瘤中量化基质金属蛋白酶激活的潜力，并为多中心试验奠定了基础 MMPPET/CT成像对AAA危险分层的价值

Abstract Abdominal aortic aneurysms (AAA) are responsible for 10,000 documented deaths every year in the US. While most aneurysms are asymptomatic, highly lethal complications, rupture and dissection do occur in a subset of patients. Aneurysm diameter is the best-known predictor of its propensity to rupture, and accordingly, aneurysm repair is recommended for large, or symptomatic AAA. However, many ruptures occur in smaller aneurysms that do not meet the criteria for repair; and conversely, some larger aneurysms do not rupture. AAA treatment remains limited to surgical or endovascular repair, as several promising medical therapies have failed in clinical studies. As such, novel tools (e.g., molecular imaging) are needed to better risk stratify patients, develop effective medical therapies, and monitor therapeutic effectiveness. Matrix metalloproteinases (MMP) activation promotes vascular remodeling in AAA, in part through degradation of elastin and other matrix proteins. Our previous studies have established the feasibility of MMP-targeted imaging to detect vascular remodeling by micro single photon emission computed tomography (SPECT)/CT in murine models of aneurysm. However, a number of limitations of the SPECT tracer and technology precluded clinical translation for vascular imaging. To address these limitations, we developed a novel family of MMP- targeted tracers (RYM) with improved pharmacokinetics, including a first in the class positron emission tomography (PET) tracer, 64Cu-RYM2. Here, we seek to further develop, evaluate, and clinically translate 64Cu-RYM2 for first in human imaging studies in AAA, hypothesizing that MMP PET/CT imaging with 64Cu- RYM2 can detect AAA MMP activity. Our specific aims are to evaluate 64Cu-RYM2 binding to human AAA tissue; address 64Cu-RYM2 pharmacokinetics and imaging performance in murine AAA in relation to tissue MMP activity; and translate 64Cu-RYM2 for human AAA imaging. Leveraging the resources and complementary expertise of the PIs and co-investigators at Yale School of Medicine and Washington University, including an NIBIB-funded P41- center at Washington University, these studies will establish the potential of 64Cu-RYM2 to quantify MMP activation in human AAA, and set the stage for a multi-center trial of MMP PET/CT imaging for AAA risk stratification.