Synthesis of 18F-fluoroalkyl-beta-D-glucosides and their evaluation as tracers for sodium-dependent glucose transporters.

Unlabelled: Three omega-(18)F-fluoro-n-alkyl-beta-D-glucosides (alkyl = ethyl (5a)), n-butyl (5b), and n-octyl (5c)) were synthesized and evaluated as potential substrates for the sodium/D-glucose cotransporter SGLT1.

Methods: The ligands were prepared by (18)F-fluoride displacement of the corresponding tetraacetyl-protected tosylate alkylglucoside precursors in CH(3)CN, followed by hydrolysis of the protective acetate esters with NaOMe/MeOH. Transport of the nonradioactive analogs 5a, 5b, and 5c by the human sodium-D-glucose cotransporter hSGLT1 was characterized in vitro in oocytes of Xenopus laevis that expressed hSGLT1. The biodistribution of the tracers was determined in mice and the presence of metabolites in the blood was investigated. Compound 5a was also evaluated in mice pretreated with phlorizin. The intrarenal distribution of 5a in mice kidney was visualized using autoradiography.

Results: The radiochemical yield of 5a, 5b, and 5c was in the range of 8%-15% (end of bombardment) with a total synthesis time of 90 min. The in vitro evaluation after expression of the hSGLT1 showed that 2'-fluoroethyl-beta-D-glucoside (5a) was transported with similar Michaelis-Menten K(m) and V(max) (maximum velocity) values as compared with methyl-alpha-D-glucopyranoside (alpha MDG). The more lipophilic compounds 5b and 5c were not transported but inhibited transport of alpha MDG. In vivo tissue distribution in mice revealed that 5a, 5b, and 5c were cleared mainly by the renal pathway and that 5a showed a significantly higher accumulation in the kidneys and a slower renal excretion as compared with 5b and 5c. Compound 5a was retained mainly in the renal outer medulla containing S3 segments of proximal tubules and the accumulation could be blocked by phlorizin pretreatment. Compound 5c passed the blood-brain barrier to some extent.

Conclusion: The data indicate that 2'-(18)F-fluoroethyl-beta-D-glucoside (5a) is a specific tracer of Na(+)-dependent glucose transport that may be used to visualize this transport activity in the S3 segments of renal proximal tubules.