With 17.6 million of individuals / year, cardiovascular diseases represent the first cause of death in the world, the majority of those deaths being attributed to coronary artery disease (CAD). The underlying mechanism of CAD is the development of atherosclerotic plaques within the wall of coronary arteries. General risk factors that allow initial risk stratification are well known, but it remains a major challenge to identify individual patients before the occurrence of acute clinical events. It is the realization that so called ‘high-risk’ or ‘vulnerable’ atherosclerotic plaques are responsible for the majority of these events, that has motivated the development of diagnostic strategies to predict in an early stage whether a specific patient will develop a life-threatening event or not. For one, molecular imaging has emerged as a tool to identify and visualize biological aspects implicated in atherosclerotic plaque vulnerability. The final goal of this project is to develop and translate to the clinic an imaging agent dedicated to the detection of vulnerable plaques in nuclear medicine departments. The term ‘vulnerable plaque’ is used to refer to atherosclerotic lesions that are responsible for life-threatening thrombotic complications. As rupture of thin-capped fibro-atheroma (TCFA) with large lipidic and necrotic cores and intense inflammatory process is the major underlying substrate, most anatomic and molecular imaging and therapeutic strategies are focusing on this specific lesion type. However, other plaque types such as eroded lesions can also give rise to thrombotic events. The prevalence of these lesions has increased so that they are now considered to be responsible for 30-40% of acute coronary syndromes (ACS). In order to identify all high-risk patients, the ideal imaging tracer should thus be able to detect both types of vulnerable lesions. Indeed, an imaging agent dedicated to non-invasive imaging of atherothrombosis that could accurately detect high risk TCFA and eroded atherosclerotic plaques and thereby enable preventive therapy to be implemented to avoid a heart attack would address a major unmet clinical need. More importantly, it will also greatly enhance the quality of at-risk patient care and treatment. Pro-thombotic factors are expressed in both main types of vulnerable lesions (TCFA and eroded lesions), and are key drivers of the thrombotic process that is responsible for acute coronary symptoms. They therefore constitute attractive targets for atherothrombosis imaging. Two of the partners have previously developed a first generation of single-domain antibody (sdAb) derived imaging agents targeting the inflammatory process that characterizes TCFA, that is currently under clinical transfer. The aim of this project is to develop and fully characterize a second generation of sdAb-derived atherosclerosis imaging agents with potentially broader application for atherothrombosis. To fulfill this objective they are collaborating with a third partner that is an expert in hematology. the project will be subdivided into 8 tasks, from the generation of the sdAb to their in vivo evaluation in mice using state of the art preclinical nuclear imaging systems.