Detection of Hypoxia by [ 18 F]EF5 in Atherosclerotic Plaques in Mice

Abstract

Objective— Atherosclerotic plaques with large lipid cores and inflammation contain regions of hypoxia. We examined the uptake of 2-(2-nitro- 1 H-imidazol-1-yl)- N -(2,2,3,3,3-pentafluoropropyl) acetamide ([ 18 F]EF5), a specific marker of hypoxia labeled for positron emission tomography, in mouse atherosclerotic plaques. Methods and Results— Atherosclerotic mice of 2 different genetic backgrounds (low-density lipoprotein receptor −/− apolipoprotein B 100/100 and insulin-like growth factor II/low-density lipoprotein receptor −/− apolipoprotein B 100/100 ) were first fed a Western diet to induce development of plaques with variable phenotypes and then injected with [ 18 F]EF5. C57BL/6N mice served as controls. Aortas were dissected for biodistribution studies, autoradiography, histology, and immunohistochemistry. Uptake of [ 18 F]EF5 was significantly higher in the aortas of mice with large atherosclerotic plaques than in the C57BL/6N controls. Furthermore, autoradiography demonstrated, on average, 2.0-fold higher [ 18 F]EF5 uptake in atherosclerotic plaques than in the adjacent normal vessel wall. Hypoxia in plaques was verified by using an EF5 adduct-specific antibody and pimonidazole. The blood clearance of [ 18 F]EF5 was slow, with blood radioactivity remaining relatively high up to 180 minutes after injection. Conclusion— Large atherosclerotic plaques in mice contained hypoxic areas and showed uptake of [ 18 F]EF5. Despite its slow blood clearance, the high uptake of [ 18 F]EF5 in plaques suggested that plaque hypoxia is a potential target for identifying high-risk plaques noninvasively.