Objective: Mannose receptor CD206 is expressed on alternatively activated macrophages1 . The aim of this study, was to develop a new 18F-labelled mannosylated dextran derivative, [18F]AlF-NOTA-DCM, for PET imaging of macrophage mannose receptor (MMR), and to evaluate its feasibility to detect inflammation.

Methods: DCM consisting a dextran backbone, cysteine and mannose moieties was synthesized as previously described2. For initial cell binding studies, a fluorophore Alexa488 tetrafluorophenyl ester was conjugated to DCM precursor in phosphate-buffered saline by 15 minutes incubation at room temperature (1 mg/mL). Then, human blood monocytes were in vitro polarized into M1 and M2 macrophages, and binding of Alexa488-DCM was evaluated by flow cytometry. For PET studies, DCM was first conjugated with 1,4,7 triazacyclononane-1,4,7 triacetic acid (NOTA) chelator. 18F was first attached to Aluminum to form Al18F, and then incubated with NOTA-DCM at 100°C for 13 minutes. In vivo stability of intravenously injected [18F]AlF-NOTA-DCM was assessed in healthy C57BL/6NRJ mice and high-performance liquid chromatography (HPLC) analysis of plasma samples. Feasibility of [18F]AlF-NOTA-DCM to detect inflammation was evaluated in a Complete Freund’s Adjuvant induced mouse model of lymph node and foot pad inflammation.

Results: The flow cytometry showed that M2 macrophages expressing MMR clearly took up Alexa488-DCM, whereas M1 macrophages lacking MMR did not show uptake (Fig. 1b). [18F]AlF-NOTADCM (25 kDa, Fig. 1a) was synthesized with >99% radiochemical purity and stability shelf life of 4 hours. Tracer was highly stable in mouse blood circulation (at 10 min post-injection 90%±6 of plasma radioactivity was from intact tracer). In vitro blocking study with excess of unlabeled DCM on inflamed lymph node tissue section confirmed that [18F]AlF-NOTA-DCM binding was specific to CD206+ macrophages. With 18F-FDG as reference, PET/CT revealed that [18F] AlF-NOTA-DCM visualized the inflamed foci (TBR 9.60±4.02) with a rapid blood clearance and the highest radioactivity concentration in liver, spleen and bone marrow, respectively. H&E and CD206 staining confirmed the uptake in inflamed area.

Conclusion: A new macrophage mannose receptor-targeted radiotracer [18F]AlF-NOTA-DCM was successfully developed and showed promising results in preclinical studies to detect inflammation. Further studies in inflammation models are warranted