Synthesis and biological evaluation of (11)C-labeled beta-galactosyl triazoles as potential PET tracers for in vivo LacZ reporter gene imaging.

In our aim to develop LacZ reporter probes with a good retention in LacZ expressing cells, we report the synthesis and preliminary evaluation of two carbon-11 labeled beta-galactosyl triazoles 1-(beta-d-galactopyranosyl)-4-(p-[(11)C]methoxyphenyl)-1,2,3-triazole ([(11)C]-6) and 1-(beta-d-galactopyranosyl)-4-(6-[(11)C]methoxynaphthyl)-1,2,3-triazole ([(11)C]-13). The precursors for the radiolabeling and the non-radioactive analogues (6 and 13) were synthesized using straightforward 'click' chemistry. In vitro incubation experiments of 6 with beta-galactosidase in the presence of o-nitrophenyl beta-d-galactopyranoside (ONPG) showed that the triazolic compound was an inhibitor of beta-galactosidase activity. Radiolabeling of both precursors was performed using [(11)C]methyl iodide as alkylating agent at 70 degrees C in DMF in the presence of a small amount of base. The logP values were -0.1 and 1.4, respectively, for [(11)C]-6 and [(11)C]-13, the latter therefore being a good candidate for increased cellular uptake via passive diffusion. Biodistribution studies in normal mice showed a good clearance from blood for both tracers. [(11)C]-6 was mainly cleared via the renal pathway, while the more lipophilic [(11)C]-13 was excreted almost exclusively via the hepatobiliary system. Despite the lipophilicity of [(11)C]-13, no brain uptake was observed. Reversed phase HPLC analysis of murine plasma and urine revealed high in vivo stability for both tracers. In vitro evaluation in HEK-293T cells showed an increased cell uptake for the more lipophilic [(11)C]-13, however, there was no statistically higher uptake in LacZ expressing cells compared to control cells.