title: Synthesis and biological evaluation of (11)C-labeled beta-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 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.
authors.affiliation: Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Herestraat 49 bus 821, BE-3000 Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.forename: Jan
authors.initials: J
authors.lastname: Cleynhens
authors.forename: Christophe
authors.initials: C
authors.lastname: Deroose
authors.forename: Tjibbe
authors.initials: T
authors.lastname: de Groot
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Ibrahimi
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Alfons
authors.initials: A
authors.lastname: Verbruggen
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D002460:Cell Line; D002463:Cell Membrane Permeability; D005690:Galactose / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D007668:Kidney / Q000166:cytology; D007763:Lac Operon; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002250:Carbon Radioisotopes; D011868:Radioisotopes; D014230:Triazoles; D001616:beta-Galactosidase; D005690:Galactose