Summary Atherosclerosis is a progressive disease characterized by the development of lipid-rich, inflammatory plaque lesions within vessel walls. It is the underlying basis of cardiovascular diseases including myocardial infarction, stroke, and peripheral arterial disease. However, the ability to reliably detect the vulnerable plaque and identify high-risk patients has been a challenge. Further, there is no imaging agent to detect the eroded plaques, a less- known subtype accounting for one third of clinical events. Chemokines and chemokine receptors play important roles in atherosclerosis from initialization to clinical event by directing leukocyte trafficking. We have developed chemokine receptor targeted positron emission tomography (PET) imaging agents and demonstrated the specific detection of monocyte trafficking in vivo and track plaque progression and regression. To further explore the potential of these imaging agents for translation, we would like to propose a research program to develop novel PET tracers with potential to identify vulnerable plaques, detect plaque erosion, and more importantly to track the treatment response to improve patient outcome. Specifically, we will firstly optimize the design and synthesis of a portfolio of PET tracers targeting plaque-relevant targets including CCR2, CCR5, CXCR3, CD44, and TLR2 to improve the radiolabeling and scale-up capability through controlled radiochemistry and bioconjugate chemistry, and binding affinities by varying the charge, surface chemistry and polymer coating materials. Secondly, we will perform in vivo biodistribution studies and PET imaging in atherosclerosis progression/regression and complication mouse models, as well as rabbit atherosclerosis models to assess the imaging specificity, sensitivity, and capability to track the immune cells in vivo and correlation with targets expression and plaque characteristics. Thirdly, we will assess the capability of developed imaging probes to determine treatment response for improved outcome and binding to ex vivo human plaque tissue for future translation. We propose to submit multiple exploratory investigational new drug application to FDA and have two PET tracers ready for human trials at the end of grant period. The establishment of this research program will not only promote the development of targeted PET tracers for atherosclerosis translational imaging, but also broader applications in other diseases within the NHLBI mission.