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

基本信息

批准号：
10617801
负责人：
Robert J. Gropler
金额：
$ 64.06万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10617801
关键词：
Abdominal Aortic Aneurysm Address Affect Aneurysm Aorta Aortic Aneurysm Autoradiography Binding Biodistribution Biological Biological Process Biology Blood Blood Vessels Cell Density Cessation of life Characteristics Clinical Clinical Research DCNU Detection Diameter 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 Detection Operative Surgical Procedures Pathogenesis Patients Performance Play Positron-Emission Tomography Practice Guidelines Predictive Value Production Property Proteins Radioisotopes Radiometry Recommendation 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 fluorodeoxyglucose positron emission tomography 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

项目摘要

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.

抽象的腹主动脉瘤 (AAA) 每年导致 10,000 例死亡我们。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动脉瘤中。患者的子集。动脉瘤直径是其破裂倾向的最著名的预测指标，并且因此，建议对较大或有症状的 AAA 进行动脉瘤修复术。但也有不少裂痕发生于不符合修复标准的较小动脉瘤；相反，一些较大的动脉瘤不破裂。 AAA 的治疗仍然仅限于手术或血管内修复，因为一些有前途的医疗方法治疗在临床研究中失败了。因此，需要新的工具（例如分子成像）来更好地应对风险对患者进行分层，开发有效的药物疗法并监测治疗效果。矩阵金属蛋白酶 (MMP) 激活促进 AAA 中的血管重塑，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立了 MMP 靶向的可行性通过微型单光子发射计算机断层扫描 (SPECT)/CT 成像检测血管重塑小鼠动脉瘤模型。然而，SPECT 示踪剂和技术的一些局限性排除了血管成像的临床翻译。为了解决这些限制，我们开发了一个新型的 MMP-家族具有改进的药代动力学的靶向示踪剂 (RYM)，包括同类首创的正电子发射断层扫描 (PET) 示踪剂，64Cu-RYM2。在这里，我们寻求进一步开发、评估和临床转化 64Cu-RYM2 首次用于 AAA 人体成像研究，假设使用 64Cu- 进行 MMP PET/CT 成像 RYM2可以检测AAA MMP活性。我们的具体目标是评估 64Cu-RYM2 与人类 AAA 的结合组织;解决小鼠 AAA 中与组织相关的 64Cu-RYM2 药代动力学和成像性能基质金属蛋白酶活性；并将 64Cu-RYM2 翻译用于人类 AAA 成像。充分利用资源和耶鲁大学医学院和华盛顿的 PI 和联合研究者的专业知识互补大学，包括 NIBIB 资助的华盛顿大学 P41 中心，这些研究将建立 64Cu-RYM2 量化人类 AAA 中 MMP 激活的潜力，并为多中心试验奠定了基础用于 AAA 风险分层的 MMP PET/CT 成像。