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.