In Vitro and In Vivo Characterization of 2-Deoxy-2-18F-Fluoro-d-Mannose as a Tumor-Imaging Agent for PET

Abstract

2-Deoxy-2-(18)F-fluoro-d-mannose ((18)F-FDM) is an (18)F-labeled mannose derivative and a stereoisomer of (18)F-FDG. Our preliminary study demonstrated that (18)F-FDM accumulated in tumors to the same extent as (18)F-FDG, with less uptake in the brain and faster clearance from the blood. However, detailed studies on the uptake of (18)F-FDM in tumors have not been conducted. We undertook this study to establish a practical method of (18)F-FDM synthesis based on an (18)F-nucleophilic substitution (SN2) reaction and to advance the biologic characterization of (18)F-FDM for potential application as a tumor-imaging agent. We synthesized 4,6-O-benzylidene-3-O-ethoxymethyl-1-O-methyl-2-O-trifluoromethanesulfonyl-β-D-glucopyranoside as a precursor for the nucleophilic synthesis of (18)F-FDM. The precursor was radiofluorinated with (18)F-KF/Kryptofix222, followed by removal of the protecting groups with an acid. (18)F-FDM was purified by preparative high-performance 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 (18)F-FDM were examined in Donryu rats bearing AH109A tumor cells by biodistribution studies and imaging with a small-animal PET system. We radiosynthesized (18)F-FDM in sufficient radiochemical yields (50%-68%) with excellent purities (97.6%-98.7%). (18)F-FDM was phosphorylated rapidly by hexokinase, resulting in 98% conversion into (18)F-FDG-6-phosphate within 30 min. Tumor cells showed significant uptake of (18)F-FDM with time in vitro, and uptake was dose-dependently inhibited by D-glucose. (18)F-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 (18)F-FDM (quasi-standardized uptake value, 2.83 ± 0.22) to be the same as that of (18)F-FDG (2.40 ± 0.30), but the brain uptake of (18)F-FDM (1.89 ± 0.13) was ≈ 30% lower than that of (18)F-FDG (2.63 ± 0.26). We prepared (18)F-FDM with good radiochemical yield and purity by an SN2 reaction. We demonstrated that (18)F-FDM 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 (18)F-FDM has almost the same potential as (18)F-FDG for PET tumor imaging, with better advantages with regard to the imaging of brain tumors.