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

Abstract

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-F-18-fluoroglutamine (F-18-FGln) allows quantification of glutamine consumption in vivo. Here, we investigated uptake of F-18-FGln by atherosclerotic lesions in mice and compared the results with those obtained using the glucose analog 2-deoxy-2-F-18-fluoro-D-glucose (F-18-FDG). Uptake of F-18-FGln and F-18-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 F-18-FGln or F-18-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 F-18-FGln was low. PET/CT detected lesions in the aortic arch, with a target-to-background ratio (SUVmax, aortic arch/SUVmean, blood) of 1.95 +/- 0.42 (mean +/- standard deviation). Gamma counting revealed that aortic uptake of F-18-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 F-18-FGln (2.90 +/- 0.42) was significantly higher than that of F-18-FDG (1.93 +/- 0.22, P = 0.004). Immunohistochemical staining confirmed that F-18-FGln uptake in plaques co-localized with glutamine transporter SLC7A7-positive macrophages. Collectively these data show that the F-18-FGln PET tracer detects inflamed atherosclerotic lesions. Thus, exploiting glutamine consumption using F-18-FGln PET may have translational relevance for studying atherosclerotic inflammation.