GLUCOSE-TRANSPORTER PROTEIN-INDEPENDENT TUMOR-CELL ACCUMULATION OF FLUORINE-18-AFDG, A LIPOPHILIC FLUORINE-18-FDG ANALOG

Fluorine-18-fluorodeoxyglucose (FDG) is used clinically for tumor diag nosis, but its mechanism of accumulation in tumor cells is complicated because two factors, glucose transporter protein (GLUT) and hexokinas e, govern [F-18]FDG uptake directly, We selected a lipophilic [F-18]FD G analog, 1,3,4,6-tetra-acetyl-2-[F-18]-2-deoxy-D-glucose ([F-18]AFDG) , to regulate the effects of hexokinase and evaluated its characterist ics in an in vitro cell culture system, Methods: Fluorine-18-AFDG was synthesized by the method used to produce [F-18]FDG, as an intermediat e of [F-18]FDG, Fluorine-18-AFDG uptake study was performed with LS180 tumor cells, and its metabolites were also investigated by thin-layer chromatography. To evaluate the relationship between [F-18]AFDG and G LUT, we also examined [F-18]AFDG uptake in the presence of cytochalasi n B or with increased medium glucose concentration, The effects of low ered temperature (4 degrees C) on [F-18]AFDG uptake were also investig ated, Results: Fluorine-l8-AFDG (lipophilicity: octanol/water 3.5) upt ake was 3.3-fold higher than that of [F-18]FDG, Metabolic analysis sho wed that [F-18]AFDG was extremely stable in the incubation medium but was quickly hydrolyzed and metabolized to 2-fluoro-[F-18]-2-deoxy-D-gl ucose-6-phosphate ([F-18]FDG-6P) in tumor cells, Fluorine-18-FDG-6P ac counted for approximately 45% of the total radioactivity after a 60-mi n incubation of [F-18]AFDG, Incubation with 50 mu M cytochalasin B did not affect [F-18]AFDG uptake. In medium with double the control gluco se level, [F-18]FDG uptake was decreased by about 50%, but [F-18]AFDG uptake was not affected, Fluorine-18-AFDG uptake and [F-18]FDG-GP prod uction did not show saturation and increased linearly with addition of a 10-fold higher concentration of [F-18]AFDG. Lowered incubation temp erature caused decreased [F-18]AFDG uptake due to reduced [F-18]FDG-GP production, Conclusion: Fluorine-18-AFDG rapidly penetrated the cell membrane as a result of its high lipophilicity and was metabolized to [F-18]FDG-GP within cells, Fluorine-18-AFDG was thus characterized as ''GLUT-independent [F-18]FDG''.