Ga68-DOTATATE PET imaging of plaque inflammation

项目摘要 动脉粥样硬化性心血管疾病（CVD）是世界范围内发病率和死亡率的主要原因。之间 动脉粥样硬化形成中涉及的几种细胞类型和过程，巨噬细胞在动脉粥样硬化形成中的作用， 高风险斑块已被充分确立和表征。在过去的15年里，我们做出了巨大努力， 开发和验证非侵入性成像，以量化斑块巨噬细胞，并改善CVD患者 管理即使在今天，影像学的作用继续被提倡，以更好地确定动脉粥样硬化 18F-FDG PET是一种非侵入性的平移成像， 广泛使用和验证的技术，以量化体内斑块巨噬细胞。然而，血管18F-FDG PET 仍然有几个重要的限制。例如，虽然18F-FDG血管壁积聚已经被证实是一种治疗方法， 与斑块炎症一致相关，摄取不是巨噬细胞特异性的， 其他因素，如缺氧和血管密度。为了克服这些限制，几种新型PET 目前， 正在调查68 Ga-DOTATATE是一种新的PET示踪剂，最近被FDA批准用于改善 生长抑素受体2（SSTR 2）阳性神经内分泌肿瘤的检测。SSTR 2也是 在活化的斑块巨噬细胞上过表达。初步研究发现，68 Ga-DOTATATE 在动脉粥样硬化小鼠的富含巨噬细胞的斑块中积累。回顾性分析证实， 癌症患者动脉粥样硬化血管壁中的累积。在这些先前研究的基础上，我们 建议建立和翻译68 Ga-DOTATATE作为动脉粥样硬化的特异性，非侵入性标志物 噬斑巨噬细胞在PET/CT对动脉粥样硬化小鼠的机制研究的同时，我们将翻译 在大型动物（兔）和冠状动脉粥样硬化患者中使用组合式PET/MR扫描仪进行的68 Ga-DOTATATE PET 动脉粥样硬化68 Ga-DOTATATE在对这种具有挑战性的血管区域进行成像时可能特别有用， 其中18F-FDG PET是众所周知的困难，因为强的，非特异性的心肌背景摄取。 我们的实验室深入参与了用于冠状动脉粥样硬化成像的平移PET/MRI， 开发创新的运动校正、部分容积校正算法和动态PET成像， 改善冠状动脉中PET示踪剂的摄取（R 01 HL 071021，PI Fayad）。我们预计 建立68 Ga-DOTATATE PET可能有助于改善CVD患者的管理， 评估新的抗动脉粥样硬化化合物，并在未来，证明有助于提高诊断 其他CVD条件虽然这项建议超出了我们的工作范围，但它是更广泛、 前瞻性临床试验研究68 Ga-DOTATATE PET和其他有前景的 CVD事件的成像标记物。

PROJECT SUMMARY Atherosclerotic cardiovascular disease (CVD) is the main cause of morbidity and mortality worldwide. Among the several cell types and processes involved in atherogenesis, the role of macrophages in the formation of high-risk plaques is well established and characterized. The past 15 years have seen tremendous efforts to develop and validate non-invasive imaging to quantify plaque macrophages and improve CVD patients management. Even nowadays, the role of imaging continues to be advocated to better define atherosclerosis and to improve assessment of therapeutic regimens.18F-FDG PET is a non-invasive, translational imaging technique widely used and validated to quantify plaque macrophages in vivo. However, vascular 18F-FDG PET still carries several important limitations. For example, while 18F-FDG vessel wall accumulation has been consistently correlated to plaque inflammation, uptake is not specific for macrophages, and can be influenced by other factors, such as hypoxia and vascular density. To overcome these limitations, several novel PET tracers more specific to unique molecules, receptors and cells involved in plaque inflammation are currently being investigated. 68Ga-DOTATATE is a novel PET tracer, recently approved by the FDA to improve detection of somatostatin receptor 2 (SSTR2) -positive neuroendocrine tumors. SSTR2s are also overexpressed on activated plaque macrophages. Preliminary studies have found 68Ga-DOTATATE to accumulate in macrophage-rich plaques in atherosclerotic mice. Retrospective analyses have confirmed accumulation in the atherosclerotic vessel wall in cancer patients. Building on these previous studies, we propose to establish and translate 68Ga-DOTATATE as a specific, non-invasive marker of atherosclerotic plaque macrophages. In parallel with mechanistic studies in atherosclerotic mice on PET/CT, we will translate 68Ga-DOTATATE PET on a combined PET/MR scanner in large animals (rabbits) and patients with coronary atherosclerosis. 68Ga-DOTATATE may be particularly useful when imaging this challenging vascular territory, where 18F-FDG PET is notoriously difficult because of the strong, non-specific myocardial background uptake. Our laboratory is deeply involved in translational PET/MRI for imaging of coronary atherosclerosis, by developing innovative motion correction, partial volume correction algorithms and dynamic PET imaging to improve PET tracers uptake in the coronary arteries (R01 HL071021, PI Fayad). We anticipate that establishing 68Ga-DOTATATE PET may allow improving the management of CVD patients, the quantitative assessment of novel anti-atherosclerotic compounds, and, in the future, prove useful to improve diagnosis of other CVD conditions. While beyond the scope of our work, this proposal is the basis for more extensive, prospective clinical trials investigating the predictive value of 68Ga-DOTATATE PET and other promising imaging markers for CVD events.