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

AAA 中 MMP 激活的 PET 成像：首次人体评估

• 批准号: 10371169
• 负责人: Robert J. Gropler
• 金额: $ 64.94万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371169
• 关键词: Abdominal Aortic Aneurysm; Address; Affect; Aneurysm; Aorta; Aortic Aneurysm; Autoradiography; Binding; Biodistribution; Biological; Biological Process; Biology; Blood; Blood Vessels; Caliber; Cell Density; Cessation of life; Characteristics; Clinical; Clinical Research; Conflict (Psychology); DCNU; Detection; Disease; Dissection; Donor person; Drug Kinetics; Elastin; Elastin Fiber; Elderly; Evaluation; Evolution; Extracellular Matrix Degradation; Extracellular Matrix Proteins; Family; Funding; Half-Life; Histologic; Hour; Human; Image; In Vitro; Inflammation; Isotope Labeling; Link; Matrix Metalloproteinases; Measurement; Medical; Methods; Monitor; Morbidity - disease rate; Multicenter Trials; Multimodal Imaging; Mus; National Institute of Biomedical Imaging and Bioengineering; Non-Invasive Cancer Detection; Operative Surgical Procedures; Pathogenesis; Patients; Performance; Play; Positron-Emission Tomography; Practice Guidelines; Predictive Value; Production; Property; Proteins; Radioisotopes; Radiometry; Research Personnel; Resources; Risk; Risk Factors; Rupture; Ruptured Abdominal Aortic Aneurysm; Safety; Shipping; Signal Transduction; Site; Smoker; Smooth Muscle Myocytes; Species Specificity; Specificity; Specimen; Technology; Tissues; Tracer; Translating; Universities; Vascular Smooth Muscle; Vascular remodeling; Washington; X-Ray Computed Tomography; aged; clinical translation; comorbidity; drug development; first-in-human; high risk; imaging modality; imaging study; improved; in vivo; medical schools; men; microPET/CT; microSPECT; molecular imaging; mortality; mouse model; novel; novel strategies; patient stratification; patient subsets; radiotracer; repaired; risk stratification; screening; single photon emission computed tomography; targeted imaging; temporal measurement; therapeutic effectiveness; tool; ultrasound; uptake; volunteer

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.

摘要 腹主动脉瘤（AAA）每年造成10，000例有记录的死亡， 我们虽然大多数动脉瘤是无症状的，但高致命性并发症、破裂和夹层确实发生在动脉瘤患者中。 患者的子集。动脉瘤直径是其破裂倾向的最佳预测因子， 因此，建议对较大或有症状的AAA进行动脉瘤修复。然而，许多断裂 发生在不符合修复标准的较小动脉瘤中;相反，一些较大的动脉瘤 不要破裂。AAA治疗仍然局限于外科手术或腔内修复术，因为一些有前途的医疗 治疗在临床研究中失败了。因此，新颖的工具（例如，分子成像），以更好地风险 对患者进行分层，开发有效的医学疗法，并监测治疗效果。矩阵 基质金属蛋白酶（MMP）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。我们以前的研究已经建立了MMP靶向治疗的可行性， 通过微型单光子发射计算机断层扫描（SPECT）/CT成像检测血管重塑， 动脉瘤的小鼠模型。然而，SPECT示踪剂和技术的许多限制排除了 血管成像的临床翻译。为了解决这些局限性，我们开发了一个新的MMP家族， 靶向示踪剂（RYM）具有改善的药代动力学，包括一流的正电子发射 断层扫描（PET）示踪剂64 Cu-RYM 2。在这里，我们寻求进一步发展，评估和临床翻译 64 Cu-RYM 2首次用于AAA的人体成像研究，假设使用64 Cu-RYM 2的MMP PET/CT成像 RYM 2可检测AAA MMP活性。我们的具体目标是评估64 Cu-RYM 2与人AAA的结合 组织;说明64 Cu-RYM 2在小鼠AAA中的药代动力学和成像性能与组织的关系 MMP活性;并翻译64 Cu-RYM 2用于人AAA成像。利用资源和 耶鲁医学院和华盛顿的PI和合作研究者的互补专业知识 包括华盛顿大学NIBIB资助的P41中心，这些研究将建立 64 Cu-RYM 2定量人AAA中MMP活化的潜力，并为多中心试验奠定基础。 MMP PET/CT成像用于AAA风险分层。