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Synthesis and Biologic Evaluation of ¹¹C-Methyl-D-Glucoside, a Tracer of the Sodium-Dependent Glucose Transporters

¹ Laboratory of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, and Department of Nuclear Medicine, University of Leuven, Leuven, Belgium
² Institute of Anatomy and Cell Biology, Bayerische Julius-Maximilians-Universität, Würzburg, Germany

This study aimed to synthesize and to evaluate the biologic characteristics of ¹¹C labeled methyl-D-glucoside, a nonmetabolizable tracer that is selectively transported by sodium-dependent glucose transporters (SGLTs). Methods:¹¹C-Methyl-D-glucoside was prepared by methylation of glucose with ¹¹C-methyl triflate and was obtained as a mixture of anomers that were separated with high-performance liquid chromatography. The biodistribution of both the D- and L-isomers was determined in mice, and the presence of metabolites in the blood was investigated. The intrarenal distribution of ¹¹C-methyl-D-glucoside in mouse kidneys was visualized using autoradiography. Transport of -methyl-D-glucoside and ß-methyl-D-glucoside by the human sodium-D-glucose cotransporter hSGLT1 was characterized after expression of hSGLT1 in oocytes of Xenopus laevis. Results: The developed preparation procedure provided ¹¹C-methyl-D-glucoside in a total synthesis time of 20 min and a yield of 30% (decay corrected). The - and ß-anomers of methyl-D-glucoside were reabsorbed from the primary urinary filtrate and showed only a minimal urinary excretion. Because methyl-L-glucoside was not reabsorbed and the reabsorption of methyl-D-glucoside was blocked by phlorizin, sodium-D-glucose cotransporters were critically involved. ß-Methyl-D-glucoside was accumulated in the kidneys to a higher extent than the -anomer, suggesting that the basolateral efflux from the tubular cells is slower for the ß-anomer. Autoradiography showed that methyl-D-glucoside was accumulated throughout the renal cortex, suggesting that both sodium-D-glucose cotransporters expressed in kidney, SGLT1 and SGLT2, are involved in the uptake. The tracer was found to be metabolically stable and did not accumulate in red blood cells, which indicates that methyl-D-glucoside is not transported by the sodium-independent transporter GLUT1. Electrical measurements in Xenopus oocytes revealed that -methyl-D-glucoside and ß-methyl-D-glucoside are transported by the human SGLT1 transporter with similar maximal transport rates and apparent Michaelis–Menten constant values. Conclusion:¹¹C-Methyl-D-glucoside is a selective tracer of sodium-dependent glucose transport and can be used to visualize the function of this transporter with PET in vivo.

Key Words: sodium-dependent glucose transporter • methylglucoside • PET • ¹¹C

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