Synthesis and biologic evaluation of (11)c-methyl-d-glucoside, a tracer of the sodium-dependent glucose transporters.
This study aimed to synthesize and to evaluate the biologic characteristics of (11)C labeled methyl-D-glucoside, a nonmetabolizable tracer that is selectively transported by sodium-dependent glucose transporters (SGLTs).


METHODS
(11)C-Methyl-D-glucoside was prepared by methylation of glucose with (11)C-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 (11)C-methyl-D-glucoside in mouse kidneys was visualized using autoradiography. Transport of alpha-methyl-D-glucoside and beta-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 (11)C-methyl-D-glucoside in a total synthesis time of 20 min and a yield of 30% (decay corrected). The alpha- and beta-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. beta-Methyl-D-glucoside was accumulated in the kidneys to a higher extent than the alpha-anomer, suggesting that the basolateral efflux from the tubular cells is slower for the beta-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 alpha-methyl-D-glucoside and beta-methyl-D-glucoside are transported by the human SGLT1 transporter with similar maximal transport rates and apparent Michaelis-Menten constant values.


CONCLUSIONS
(11)C-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.
Bormans
Guy M
GM
Faculty of Pharmaceutical Sciences and Department of Nuclear Medicine, University of Leuven, Leuven, Belgium. guy.bormans@uz.kuleuven.ac.be
Van Oosterwyck
Griet
G
De Groot
Tjibbe J
TJ
Veyhl
Maike
M
Mortelmans
Luc
L
Verbruggen
Alfons M
AM
Koepsell
Hermann
H
D000818:Animals; D001345:Autoradiography / Q000379:methods; D002250:Carbon Radioisotopes / Q000097:blood / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D005069:Evaluation Studies as Topic; D051272:Glucose Transporter Type 1; D006801:Humans; D007553:Isotope Labeling / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D008757:Methylglucosides / Q000097:blood / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000493:pharmacokinetics*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism*; D009928:Organ Specificity; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000302:isolation & purification / Q000378:metabolism; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods; D011994:Recombinant Proteins / Q000378:metabolism; D014018:Tissue Distribution; D014982:Xenopus laevis
D002250:Carbon Radioisotopes; D051272:Glucose Transporter Type 1; D008757:Methylglucosides; D009004:Monosaccharide Transport Proteins; D019275:Radiopharmaceuticals; D011994:Recombinant Proteins; C495677:SLC2A1 protein, human; C495678:Slc2a1 protein, mouse; C027020:methylglucoside