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: 10226098
• 负责人: Robert J. Gropler
• 金额: $ 65.62万
• 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/10226098
• 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; Ultrasonography; 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; 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