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18-kDa translocator protein ligand 18F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice

  • Original Article
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Journal of Nuclear Cardiology Aims and scope

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.

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Abbreviations

11C-PK11195:

N-methyl-11C-(R)-1-(2-chlorophenyl)-N-(1-methyl-propyl)-3-isoquinoline carboxamide

18F-FDG:

2-18F-fluoro-2-deoxy-d-glucose

18F-FEMPA:

N-{2-[2-18F-fluoroethoxy]-5-methoxybenzyl}-N-[2-(4-methoxyphenoxy)pyridin-3-yl]acetamide

α-SMA:

Alpha-smooth muscle actin

H&E:

Hematoxylin and eosin

PET/CT:

Positron emission tomography/computed tomography

PSL/mm2 :

Photo-stimulated luminescence per square millimetre

ROI:

Region of interest

SUV:

Standardized uptake value

TSPO:

Translocator protein (18-kDa)

VSMCs:

Vascular smooth muscle cells

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Acknowledgments

The authors thank Anja Hoffmann for manuscript revising, Ville Aalto for assistance in statistical analyses and Erica Nyman, Liisa Lempiäinen, Päivi Marjamäki, Leena Tokoi-Eklund, Aake Honkaniemi, Mia Ståhle, and Jenni Virta for technical assistance.

Disclosure

AT, LL, TH, and SV were employed by Bayer Pharma AG, Berlin, Germany at the time of the study. Other authors declare no conflict of interest. The compound 18F-FEMPA is now part of the portfolio of the Piramal Imaging GmbH. The study was conducted within the Finnish Centre of Excellence in Cardiovascular and Metabolic Diseases supported by the Academy of Finland, University of Turku, Turku University Hospital and Åbo Akademi University. Funding was received from Finnish Foundation for Cardiovascular Research, Finnish Cultural Foundation/Varsinais-Suomi Regional Fund, Academy of Finland, Turku University Foundation, Ida Montin Foundation, Sigrid Jusélius Foundation and Drug Research Doctoral Programme, University of Turku Graduate School.

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Authors and Affiliations

  1. Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland

    Sanna Hellberg MSc, Johanna M. U. Silvola PhD, Max Kiugel MSc, Heidi Liljenbäck MSc, Nina Savisto PhD, Xiang-Guo Li PhD, Juhani Knuuti MD, PhD, Anne Roivainen PhD & Antti Saraste MD, PhD

  2. Turku Center for Disease Modeling, University of Turku, Turku, Finland

    Heidi Liljenbäck MSc & Anne Roivainen PhD

  3. Bayer Pharma AG, Berlin, Germany

    Andrea Thiele PhD, Lutz Lehmann PhD, Tobias Heinrich PhD & Sonja Vollmer PhD

  4. Department of Surgery, University of Turku, Turku, Finland

    Harri Hakovirta MD, PhD

  5. Department of Pathology, Turku University Hospital, Turku, Finland

    V. Jukka O. Laine MD, PhD

  6. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    Seppo Ylä-Herttuala MD, PhD

  7. Turku PET Centre, Turku University Hospital, Turku, Finland

    Juhani Knuuti MD, PhD, Anne Roivainen PhD & Antti Saraste MD, PhD

  8. Heart Center, Turku University Hospital and University of Turku, Turku, Finland

    Antti Saraste MD, PhD

  9. Institute of Clinical Medicine, University of Turku, Turku, Finland

    Antti Saraste MD, PhD

Authors
  1. Sanna Hellberg MSc
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  2. Johanna M. U. Silvola PhD
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  16. Antti Saraste MD, PhD
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Corresponding author

Correspondence to Antti Saraste MD, PhD.

Additional information

See related editorial, doi:10.1007/s12350-016-0552-x.

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Hellberg, S., Silvola, J.M.U., Kiugel, M. et al. 18-kDa translocator protein ligand 18F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice. J. Nucl. Cardiol. 24, 862–871 (2017). https://doi.org/10.1007/s12350-016-0527-y

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  • DOI: https://doi.org/10.1007/s12350-016-0527-y

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