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

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

doi:10.3389/fimmu.2022.821423

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

Front Immunol. 2022 Jan 25:13:821423. doi: 10.3389/fimmu.2022.821423. eCollection 2022.

Authors

Senthil Palani¹, Maxwell W G Miner¹, Jenni Virta¹, Heidi Liljenbäck^{1

2}, Olli Eskola¹, Tiit Örd³, Aarthi Ravindran³, Minna U Kaikkonen³, Juhani Knuuti^{1

4

5}, Xiang-Guo Li^{1

5}, Antti Saraste^{1

6}, Anne Roivainen^{1

2

4

5}

Affiliations

¹ Turku PET Centre, University of Turku, Turku, Finland.
² Turku Center for Disease Modeling, University of Turku, Turku, Finland.
³ A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
⁴ Turku PET Centre, Turku University Hospital, Turku, Finland.
⁵ InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
⁶ Heart Center, Turku University Hospital and University of Turku, Turku, Finland.

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)-4-¹⁸F-fluoroglutamine (¹⁸F-FGln) allows quantification of glutamine consumption in vivo. Here, we investigated uptake of ¹⁸F-FGln by atherosclerotic lesions in mice and compared the results with those obtained using the glucose analog 2-deoxy-2-¹⁸F-fluoro-D-glucose (¹⁸F-FDG). Uptake of ¹⁸F-FGln and ¹⁸F-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 ¹⁸F-FGln or ¹⁸F-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 ¹⁸F-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 ¹⁸F-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 ¹⁸F-FGln (2.90 ± 0.42) was significantly higher than that of ¹⁸F-FDG (1.93 ± 0.22, P = 0.004). Immunohistochemical staining confirmed that ¹⁸F-FGln uptake in plaques co-localized with glutamine transporter SLC7A7-positive macrophages. Collectively these data show that the ¹⁸F-FGln PET tracer detects inflamed atherosclerotic lesions. Thus, exploiting glutamine consumption using ¹⁸F-FGln PET may have translational relevance for studying atherosclerotic inflammation.

Keywords: 18F-fluoroglutamine; PET/CT; atherosclerosis; inflammation; macrophages.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoprotein B-100 / genetics
Atherosclerosis / diagnostic imaging*
Atherosclerosis / metabolism
Disease Models, Animal
Fluorodeoxyglucose F18
Glutamine / analogs & derivatives*
Male
Mice
Mice, Inbred C57BL
Plaque, Atherosclerotic / diagnostic imaging*
Positron Emission Tomography Computed Tomography*
Receptors, LDL / deficiency
Receptors, LDL / genetics

Substances

Apolipoprotein B-100
Receptors, LDL
Glutamine
Fluorodeoxyglucose F18

Abstract

Publication types

MeSH terms

Substances

Grants and funding