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

Abstract 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 β-galactosyl triazoles 1-(β- d -galactopyranosyl)-4-( p -[ 11 C]methoxyphenyl)-1,2,3-triazole ([ 11 C]- 6 ) and 1-(β- 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 β-galactosidase in the presence of o -nitrophenyl β- d -galactopyranoside (ONPG) showed that the triazolic compound was an inhibitor of β-galactosidase activity. Radiolabeling of both precursors was performed using [ 11 C]methyl iodide as alkylating agent at 70 °C in DMF in the presence of a small amount of base. The log  P 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.