title: Synthesis and evaluation of 18F- and 11C-labeled phenyl-galactopyranosides as potential probes for in vivo visualization of LacZ gene expression using positron emission tomography.
abstract: 3-Hydroxy-2-nitrophenyl 2,3,4,6-tetra-O-acetyl-beta-D-galactopyranoside, a derivative of the chromogenic beta-galactosidase (beta-gal) substrate o-nitrophenyl beta-D-galactopyranoside (ONPG) was synthesized using a Koenigs-Knorr glycosylation reaction. It was alkylated with 2-[(18)F]fluoroethyl triflate or [(11)C]methyl triflate, followed by deacetylation of the sugar hydroxyl groups to obtain radiolabeled 3-(2'-[(18)F]fluoroethoxy)-2-nitrophenyl beta-D-galactopyranoside ([(18)F]-2c) and 3-[(11)C]methoxy-2-nitrophenyl beta- d-galactopyranoside ([(11)C]-3c), which were evaluated as potential reporter probes for in vivo visualization of LacZ gene expression with positron emission tomography (PET). In vitro, [(18)F]- 2c and [(11)C]-3c were good substrates of beta-gal and showed, respectively, a 7.5- and 2.5-fold higher uptake into beta-gal expressing cells (LacZ cells) compared to control cells. However, reversed-phase HPLC analysis of the LacZ cell lysate and supernatant showed that labeled 3-(2'-[(18)F]fluoroethoxy)-2-nitrophenol, the hydrolysis product formed by beta-gal-mediated cleavage of [(18)F]-2c, substantially leaked out of the cells, which would lead to loss of PET signal. In a microPET study of [(18)F]-2c in a mouse with a beta-gal expressing tumor, high retention was observed in liver and kidneys, but only negligible accumulation was seen in the tumor. As a general conclusion, it can be stated that the synthesized PET tracers [ (18)F]-2c and [(11)C]-3c are not suitable for use as LacZ reporter probes. Further structural modifications to improve the diffusion over the tumor cell membrane and to increase retention in beta-gal expressing cells may lead to more favorable in vivo imaging probes.
authors.affiliation: Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Celen
authors.forename: Christophe
authors.initials: C
authors.lastname: Deroose
authors.forename: Tjibbe
authors.initials: T
authors.lastname: de Groot
authors.forename: Satish K
authors.initials: SK
authors.lastname: Chitneni
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: D002250:Carbon Radioisotopes; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D006801:Humans; D007763:Lac Operon; D009682:Magnetic Resonance Spectroscopy; D049268:Positron-Emission Tomography; D011714:Pyrans / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D011714:Pyrans