Sanna Hellberg1, Johanna M U Silvola1, Max Kiugel1, Heidi Liljenbäck1,2, Nina Savisto1, Xiang-Guo Li1, Andrea Thiele3, Lutz Lehmann3, Tobias Heinrich3, Sonja Vollmer3, Harri Hakovirta4, V Jukka O Laine5, Seppo Ylä-Herttuala6, Juhani Knuuti1,7, Anne Roivainen1,2,7, Antti Saraste8,9,10,11. 1. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland. 2. Turku Center for Disease Modeling, University of Turku, Turku, Finland. 3. Bayer Pharma AG, Berlin, Germany. 4. Department of Surgery, University of Turku, Turku, Finland. 5. Department of Pathology, Turku University Hospital, Turku, Finland. 6. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland. 7. Turku PET Centre, Turku University Hospital, Turku, Finland. 8. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland. antti.saraste@utu.fi. 9. Turku PET Centre, Turku University Hospital, Turku, Finland. antti.saraste@utu.fi. 10. Heart Center, Turku University Hospital and University of Turku, Turku, Finland. antti.saraste@utu.fi. 11. Institute of Clinical Medicine, University of Turku, Turku, Finland. antti.saraste@utu.fi.
Abstract
BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.
BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and humanatherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.
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