Macrophage mannose receptor CD206 targeting of fluoride-18 labeled mannosylated dextran: A validation study in mice

Putri Andriana; Ruth Fair-Mäkelä; Heidi Liljenbäck; Salli Kärnä; Imran Iqbal; Konstantina Makrypidi; Johan Rajander; Ioannis Pirmettis; Xiang-Guo Li; Sirpa Jalkanen; Antti Saraste; Marko Salmi; Anne Roivainen

doi:10.1007/s00259-024-06686-x

Macrophage mannose receptor CD206 targeting of fluoride-18 labeled mannosylated dextran: A validation study in mice

Eur J Nucl Med Mol Imaging. 2024 Mar 27. doi: 10.1007/s00259-024-06686-x. Online ahead of print.

Authors

Putri Andriana¹, Ruth Fair-Mäkelä^{2

3}, Heidi Liljenbäck^{1

4}, Salli Kärnä¹, Imran Iqbal¹, Konstantina Makrypidi⁵, Johan Rajander⁶, Ioannis Pirmettis⁵, Xiang-Guo Li^{1

3

7}, Sirpa Jalkanen^{3

8}, Antti Saraste^{1

9

10}, Marko Salmi^{2

3

8}, Anne Roivainen^{11

12

13

14}

Affiliations

¹ Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland.
² Institute of Biomedicine, University of Turku, Turku, Finland.
³ InFLAMES Research Flagship Center, University of Turku, Turku, Finland.
⁴ Turku Center of Disease Modeling, University of Turku, Turku, Finland.
⁵ Institute of Nuclear and Radiological Science and Technology, Energy and Safety, NCSR "Demokritos", Athens, Greece.
⁶ Turku PET Centre, Accelerator Laboratory, Åbo Akademi University, Turku, Finland.
⁷ Department of Chemistry, University of Turku, Turku, Finland.
⁸ MediCity Research Laboratory, University of Turku, Turku, Finland.
⁹ Turku PET Centre, Turku University Hospital, Turku, Finland.
¹⁰ Heart Center, Turku University Hospital and University of Turku, Turku, Finland.
¹¹ Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520, Turku, Finland. anne.roivainen@utu.fi.
¹² InFLAMES Research Flagship Center, University of Turku, Turku, Finland. anne.roivainen@utu.fi.
¹³ Turku Center of Disease Modeling, University of Turku, Turku, Finland. anne.roivainen@utu.fi.
¹⁴ Turku PET Centre, Turku University Hospital, Turku, Finland. anne.roivainen@utu.fi.

PMID: 38532026
DOI: 10.1007/s00259-024-06686-x

Abstract

Purpose: Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated mannosylated dextran derivative (Al[¹⁸F]F-NOTA-D10CM) is a new tracer for PET imaging. We report here on in vitro and in vivo validation of the tracer's ability to target the macrophage mannose receptor CD206.

Methods: First, the uptake of intravenously (i.v.) administered Al[¹⁸F]F-NOTA-D10CM was compared between wild-type (WT) and CD206^-/- knockout (KO) mice. C57BL/6N mice were injected with complete Freund's adjuvant (CFA) in the left hind leg and the uptake of Al[¹⁸F]F-NOTA-D10CM after i.v. or intradermal (i.d.) injection was studied at 5 and 14 days after CFA induction of inflammation. Healthy C57BL/6N mice were studied as controls. Mice underwent PET/CT on consecutive days with [¹⁸F]FDG, i.v. Al[¹⁸F]F-NOTA-D10CM, and i.d. Al[¹⁸F]F-NOTA-D10CM. After the last imaging, Al[¹⁸F]F-NOTA-D10CM was i.v. injected for an ex vivo biodistribution study and autoradiography of inflamed tissues. Blood plasma samples were analyzed using high-performance liquid chromatography. To evaluate the specificity of Al[¹⁸F]F-NOTA-D10CM binding, an in vitro competitive displacement study was performed on inflamed tissue sections using autoradiography. CD206 expression was assessed by immunohistochemical staining.

Results: Compared with WT mice, the uptake of Al[¹⁸F]F-NOTA-D10CM was significantly lower in several CD206^-/- KO mice tissues, including liver (SUV 8.21 ± 2.51 vs. 1.06 ± 0.16, P < 0.001) and bone marrow (SUV 1.63 ± 0.37 vs. 0.22 ± 0.05, P < 0.0001). The uptake of i.v. injected Al[¹⁸F]F-NOTA-D10CM was significantly higher in inflamed ankle joint (SUV 0.48 ± 0.13 vs. 0.18 ± 0.05, P < 0.0001) and inflamed foot pad skin (SUV 0.41 ± 0.10 vs. 0.04 ± 0.01, P < 0.0001) than in the corresponding tissues in healthy mice. The i.d.-injected Al[¹⁸F]F-NOTA-D10CM revealed differences between CFA-induced lymph node activation and lymph nodes in healthy mice. Ex vivo γ-counting, autoradiography, and immunohistochemistry supported the results, and a decrease of ~ 80% in the binding of Al[¹⁸F]F-NOTA-D10CM in the displacement study with excess NOTA-D10CM confirmed that tracer binding was specific. At 60 min after i.v. injection, an average 96.70% of plasma radioactivity was derived from intact Al[¹⁸F]F-NOTA-D10CM, indicating good in vivo stability. The uptake of Al[¹⁸F]F-NOTA-D10CM into inflamed tissues was positively associated with the area percentage of CD206-positive staining.

Conclusion: The uptake of mannosylated dextran derivative Al[¹⁸F]F-NOTA-D10CM correlated with CD206 expression and the tracer appears promising for inflammation imaging.

Keywords: Fluorine-18; Inflammation; Macrophage mannose receptor CD206; Mannosylated dextran; PET/CT.