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

2013; Society of Nuclear Medicine and Molecular Imaging; Volume: 54; Issue: 8 Linguagem: Inglês

10.2967/jnumed.112.113571

1535-5667

Shozo Furumoto, Ryo Shinbo, Ren Iwata, Yoichi Ishikawa, Kazuhiko Yanai, Takashi Yoshioka, Hiroshi Fukuda,

Cancer-related Molecular Pathways

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 (S N 2) reaction and to advance the biologic characterization of 18 F-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-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. Results: 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). Conclusion: We prepared 18 F-FDM with good radiochemical yield and purity by an S N 2 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.