AUTHOR=Palani Senthil , Miner Maxwell W. G. , Virta Jenni , Liljenbäck Heidi , Eskola Olli , Örd Tiit , Ravindran Aarthi , Kaikkonen Minna U. , Knuuti Juhani , Li Xiang-Guo , Saraste Antti , Roivainen Anne 

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

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.821423

DOI=10.3389/fimmu.2022.821423

ISSN=1664-3224

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