Exploiting Glutamine Consumption in Atherosclerotic Lesions by Positron Emission Tomography Tracer (2S,4R)-4-(18)F-Fluoroglutamine

Increased glutamine metabolism by macrophages is associated with development of atherosclerotic lesions. Positron emission tomography/computed tomography (PET/CT) with a glutamine analog (2S,4R)-4-(18)F-fluoroglutamine ((18)F-FGln) allows quantification of glutamine consumption in vivo. Here, we investigated uptake of (18)F-FGln by atherosclerotic lesions in mice and compared the results with those obtained using the glucose analog 2-deoxy-2-(18)F-fluoro-D-glucose ((18)F-FDG). Uptake of (18)F-FGln and (18)F-FDG by healthy control mice (C57BL/6JRj) and atherosclerotic low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR(−/−)ApoB(100/100)) was investigated. The mice were injected intravenously with (18)F-FGln or (18)F-FDG for in vivo PET/CT imaging. After sacrifice at 70 minutes post-injection, tracer uptake was analyzed by gamma counting of excised tissues and by autoradiography of aorta cryosections, together with histological and immunohistochemical analyses. We found that myocardial uptake of (18)F-FGln was low. PET/CT detected lesions in the aortic arch, with a target-to-background ratio (SUV(max), aortic arch/SUV(mean), blood) of 1.95 ± 0.42 (mean ± standard deviation). Gamma counting revealed that aortic uptake of (18)F-FGln by LDLR(−/−)ApoB(100/100) mice (standardized uptake value [SUV], 0.35 ± 0.06) was significantly higher than that by healthy controls (0.20 ± 0.08, P = 0.03). More detailed analysis by autoradiography revealed that the plaque-to-healthy vessel wall ratio of (18)F-FGln (2.90 ± 0.42) was significantly higher than that of (18)F-FDG (1.93 ± 0.22, P = 0.004). Immunohistochemical staining confirmed that (18)F-FGln uptake in plaques co-localized with glutamine transporter SLC7A7-positive macrophages. Collectively these data show that the (18)F-FGln PET tracer detects inflamed atherosclerotic lesions. Thus, exploiting glutamine consumption using (18)F-FGln PET may have translational relevance for studying atherosclerotic inflammation.