Introduction: Endarterectomized human atherosclerotic plaques are a valuable basis for gene expression studies to disclose novel imaging biomarkers and therapeutic targets, such as the cannabinoid receptor type 2 (CB2). In this work, CB2 is expressed on activated immune cells, which are abundant in inflamed plaques. We evaluated the CB2-specific radiotracer [C-11]RS-016 for imaging vascular inflammation in human and mouse atherosclerotic lesions. Methods: The differential gene expression of microscopically classified human carotid plaques was evaluated using quantitative polymerase chain reaction. In addition, CB2 expression levels in human plaques were investigated by in vitro autoradiography. As an appropriate animal model we used apolipoprotein E knockout mice (ApoE KO) with shear stress-induced atherosclerosis to evaluate CB2 levels in vivo. Positron emission tomography (PET) was performed with both the CB2 radioligand [C-11]RS-016 and the metabolic radiotracer [F-18]fluorodeoxyglucose ([F-18]FDG) at various time points. Retrospectively, carotids were dissected for histopathology and gene expression analysis. Results: We identified 28 human genes differentially expressed in atherosclerotic plaques compared to normal arteries of which 12 were upregulated preferentially in vulnerable plaques. The latter group included members of matrix metalloproteinase family and the T-lymphocyte activation antigens CD80 and CD86. CB2 was upregulated by 2-fold in human atherosclerotic plaques correlating with CD68 expression levels. Specific in vitro binding of [C-11]RS-016 was predominantly observed to plaques. In vivo PET imaging of ApoE KO mice revealed accumulation of[C-11]RS-016 and [F-18]FDG in atherosclerotic plaques. Development of advanced plaques with elevated CB2 and CD68 levels were found in vitro in ApoE KO mice resembling human vulnerable plaques. Conclusion: We identified human genes associated with plaque vulnerability, which potentially could serve as novel imaging or therapeutic targets. The CB2-specific radiotracer [C-11]RS-016 detected human plaques by in vitro autoradiography and accumulated in vivo in plaques of ApoE KO mice, however not exclusively in vulnerable plaques. (C) 2017 Elsevier Inc All rights reserved.