Background The present study explored the 18 kDa translocator protein radioligand [F-18]N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline (F-18-PBR06) targeting macrophages for PET imaging of atherosclerotic plaques and evaluating the vulnerability of atherosclerotic plaques toward rupture. Materials and methods F-18-PBR06 was synthesized using a Synthra RNplus module automatically. RAW264.7 cells were used for cell binding study with F-18-PBR06. In-vivo micro-PET/CT imaging for ApoE(-/-) mice and C57 mice was performed 1 h after injection of F-18-PBR06. CD68(+) and F480 immunofluorescence stainings were performed in the aorta tissues. Results In-vitro cell studies showed uptake of F-18-PBR06 to RAW264.7 cells. Micro-PET/CT imaging identified the atherosclerotic lesions in the aortic arch of ApoE(-/-) mice successfully, whereas no signal was observed in C57 mice. The ratio of plaque-to-muscle in ApoE(-/-) mice of 32 weeks was significantly higher than that in ApoE(-/-) mice of 22 weeks, which was confirmed by CD68(+) immunofluorescence staining and F480 immunofluorescence staining. Conclusion TSPO radioligand F-18-PBR06 allows noninvasive PET/CT imaging of macrophage-abundant atherosclerotic plaques as well as positive correlation between PET imagings and ex-vivo immunofluorescence staining of plaques in mice with different ages, thereby representing a potential attractive tool for evaluating the vulnerability of atherosclerotic plaques towards rupture.