Background: Sensitive detection and qualitative analysis of atherosclerotic plaques are in high demand in cardiovascular clinical settings. The leukocyte-endothelial interaction mediated by an adhesion molecule P-selectin participates in arterial wall inflammation and atherosclerosis. Methods and results: A Cu-64-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid conjugated anti-P-selectin monoclonal antibody (Cu-64_DOTA-anti-P-selectin mAb) probe was prepared by conjugating an anti-P-selectin monoclonal antibody with DOTA followed by Cu-64 labeling. Thirty-six hours prior to PET and CF fusion imaging, 3 MBq of Cu-64-DOTA-anti-P-selectin mAb was intravenously injected into low density lipoprotein receptor-deficient LdIr-/- mice. After a 180 min PET scan, autoradiography and biodistribution of Cu-64-DOTA-anti-P-selectin monoclonal antibody was examined using excised aortas. In LdIr-/- mice fed with a high cholesterol diet for promotion of atherosclerotic plaque development, PET and CT fusion imaging revealed selective and prominent accumulation of the probe in the aortic root. Autoradiography of aortas that demonstrated probe uptake into atherosclerotic plaques was confirmed by Oil red O staining for lipid droplets. In LdIr-/- mice fed with a chow diet to develop mild atherosclerotic plaques, probe accumulation was barely detectable in the aortic root on PET and CT fusion imaging. Probe biodistribution in aortas was 6.6-fold higher in LdIr-/- mice fed with a high cholesterol diet than in those fed with a normal chow diet. Cu-64-DOTA-anti-P-selectin mAb accumulated selectively in aortic atherosclerotic plaques and was detectable by PET and CT fusion imaging in LdIr-/- mice. Conclusions: P-selectin is a candidate target molecule for early-phase detection by PET and CT fusion imaging of atherosclerotic plaques. (c) 2013 Elsevier Inc. All rights reserved.