In vitro and in vivo characterization of 2-deoxy-2-¹⁸FFluoro-D- mannose as a tumor-imaging agent for PET

2-Deoxy-2-¹⁸F-fluoro-D-mannose (¹⁸F-FDM) is an ¹⁸F-labeled mannose derivative and a stereoisomer of ¹⁸F-FDG. Our preliminary study demonstrated that ¹⁸F-FDM accumulated in tumors to the same extent as ¹⁸F-FDG, with less uptake in the brain and faster clearance from the blood. However, detailed studies on the uptake of ¹⁸F-FDM in tumors have not been conducted. We undertook this study to establish a practical method of ¹⁸F-FDM synthesis based on an ¹⁸F-nucleophilic substitution (S_N2) reaction and to advance the biologic characterization of ¹⁸F-FDM for potential application as a tumor-imaging agent. Methods: We synthesized 4,6-O-benzylidene-3-O-ethoxymethyl-1-O-methyl-2-O-trifluoromethanesulfonyl- b-D-glucopyranoside as a precursor for the nucleophilic synthesis of ¹⁸F-FDM. The precursor was radiofluorinated with ¹⁸F-KF/ Kryptofix222, followed by removal of the protecting groups with an acid. ¹⁸F-FDM was purified by preparative highperformance liquid chromatography and then subjected to in vitro evaluation regarding phosphorylation by hexokinase as well as uptake and metabolism in AH109A tumor cells. The in vivo properties of ¹⁸F-FDM were examined in Donryu rats bearing AH109A tumor cells by biodistribution studies and imaging with a smallanimal PET system. Results: We radiosynthesized ¹⁸F-FDM in sufficient radiochemical yields (50%-68%) with excellent purities (97.6%-98.7%). ¹⁸F-FDM was phosphorylated rapidly by hexokinase, resulting in 98% conversion into ¹⁸F-FDG-6-phosphate within 30 min. Tumor cells showed significant uptake of ¹⁸F-FDM with time in vitro, and uptake was dose-dependently inhibited by D-glucose. ¹⁸F-FDM injected into tumor-bearing rats showed greater uptake in tumors (2.17 ± 0.32 percentage injected dose per gram [%ID/g]) than in the brain (1.42 ± 0.10 %ID/g) at 60 min after injection. PET studies also revealed the tumor uptake of ¹⁸FFDM (quasi-standardized uptake value, 2.83 ± 0.22) to be the same as that of ¹⁸F-FDG (2.40 ± 0.30), but the brain uptake of ¹⁸F-FDM (1.89 ± 0.13) was ≈30% lower than that of ¹⁸F-FDG (2.63 ± 0.26). Conclusion: We prepared ¹⁸F-FDM with good radiochemical yield and purity by an S_N2 reaction. We demonstrated that ¹⁸FFDM had adequate tumor cell uptake by a metabolic trapping mechanism and can afford high-contrast tumor images with less uptake in the brain, indicating that ¹⁸F-FDM has almost the same potential as ¹⁸F-FDG for PET tumor imaging, with better advantages with regard to the imaging of brain tumors. COPYRIGHT