title: Synthesis and preliminary evaluation of 18F- or 11C-labeled bicyclic nucleoside analogues as potential probes for imaging varicella-zoster virus thymidine kinase gene expression using positron emission tomography.
abstract: Two radiolabeled bicyclic nucleoside analogues (BCNAs) were synthesized, namely 3-(2'-deoxy-beta-d-ribofuranosyl)-6-(3-[18F]fluoroethoxyphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one ([18F]-2) and 3-(2'-deoxy-beta-d-ribofuranosyl)-6-(3-[11C]methoxyphenyl)-2,3-dihydrofuro[2,3-d]pyrimidin-2-one ([11C]-3), and evaluated as PET reporter probes for varicella-zoster virus thymidine kinase (VZV-tk) gene expression imaging in brain. [18F]-2 and [11C]-3 were synthesized starting from phenol precursor 1. The phenol precursor 1 was converted to stable as well as to radiolabeled compounds 2 and 3 using (19/18)FCH(2)CH(2)Br or (12/11)CH(3)I as alkylating agent. In vitro evaluation of [18F]-2 and [11C]-3 in 293T cells showed a 4.5 and 53-fold higher uptake, respectively, into VZV-tk gene-transduced cells compared to control cells. However, biodistribution studies in mice demonstrated low uptake of these tracers in the brain. RP-HPLC analysis of plasma and urine samples of mice injected with [11C]-3 revealed that this tracer is very stable in vivo. These data warrant further evaluation of these tracers as noninvasive imaging agents for VZV infection and VZV-tk reporter gene expression in vivo.
authors.affiliation: Laboratory for Radiopharmacy, Faculty of Pharmaceutical Sciences, K.U. Leuven, Leuven, Belgium.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Chitneni
authors.forename: Christophe M
authors.initials: CM
authors.lastname: Deroose
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Rik
authors.initials: R
authors.lastname: Gijsbers
authors.forename: Sofie J L
authors.initials: SJ
authors.lastname: Celen
authors.forename: Tjibbe J
authors.initials: TJ
authors.lastname: de Groot
authors.forename: Zeger
authors.initials: Z
authors.lastname: Debyser
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Alfons M
authors.initials: AM
authors.lastname: Verbruggen
authors.forename: Guy M
authors.initials: GM
authors.lastname: Bormans
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology*; D002250:Carbon Radioisotopes; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D015870:Gene Expression; D014645:Herpesvirus 3, Human / Q000201:enzymology*; D006801:Humans; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000235:genetics; D014018:Tissue Distribution
chemical_list: C518990:3-(2'-deoxyribofuranosyl)-6-(3-fluoroethoxyphenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2-one; C518991:3-(2'-deoxyribofuranosyl)-6-(3-methoxyphenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2-one; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D011741:Pyrimidine Nucleosides; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase