Evaluation of PET-tracers for imaging pancreatic beta cells

In both type I and type II diabetes a decrease of beta-cell mass in pancreas can be observed, but the time course, apoptotic processes as well as the regenerative capacity of these cells are widely unknown. To date a measurement of both beta cell mass and function is not possible in man and so the development of tracers for non-invasive imaging methods like PET (positron emitting tomography) remains to be done. An analogue of the clinically established sulfonylurea Glyburide, namely [ 18F]fluorodesmethoxy-glyburide ([18F]- FDMG) has already been synthesized and evaluated for its PET-imaging properties. In vitro studies elucidated uptake of the molecule into Min6 cells and stimulation of the release of insuline from rat islets. On the other hand, in vivo experiments showed low activity concentration in pancreas but high accumulation in the liver and so the signal-noise ratio was relatively low. Nevertheless, in comparison to already existing agents, [ 18F]FDMG exhibited lower liver uptake and hence better pancreas to liver uptake ratio, which is most probably due to reduced lipophilicity. Therefore, two novel [ 18F]-labeled glyburide analogues with increased hydrophilicity will be synthesized (introduction of a [ 18F]1-fluoro-3-hydroxy-2-propoxy and a [ 18F]4-fluoro-2,3-dihydroxy-1-propoxy group, respectively) and radiochemical parameters (yield, activity), lipophilicity as well as the in vitro activity in beta- cells (cell uptake, insulin secretion) will be determined. Corresponding in vivo data of PET experiments in mice (cell uptake, tissue specifity, time-activity curves, plasma protein binding, analysis of metabolites) will elucidate the suitability of these molecules for beta-cell imaging.