A p-[18F]fluoroethoxyphenyl bicyclic nucleoside analogue as a potential positron emission tomography imaging agent for varicella-zoster virus thymidine kinase gene expression.
We recently reported a new positron emission tomography (PET) reporter gene, namely, varicella-zoster virus thymidine kinase (VZV-tk) in combination, with carbon-11 or fluorine-18 labeled m-alkoxyphenyl bicyclic nucleoside analogues (BCNAs) as PET reporter probes. We now report the synthesis and evaluation of p-alkoxyphenyl-BCNA tracers ([11C]-4 and [18F]-5), which are found to be superior to the m-alkoxyphenyl-BCNA tracers. In particular, the fluorine-18 labeled tracer ([18F]-5, IC50 of 5 is 4.2 microM) shows a higher accumulation in VZV-tk expressing cells than the previously reported m-methoxyphenyl BCNA. [11C]-4 and [18F]-5 were synthesized by heating the phenol precursor 3 with 11CH 3I and 18FCH 2CH 2Br, respectively, as alkylating agents. In vitro evaluation of [11C]-4 and [18F]-5 in 293T cells showed about 14- and 54-fold higher uptake, respectively, into VZV-tk gene-transduced cells compared to control cells. LC-MS analysis confirmed the formation of monophosphate derivative of 5 upon catalysis by VZV TK. In vivo studies of this new reporter gene/probe system are in progress.
Chitneni
Satish K
SK
Molecular Small Animal Imaging Center, Laboratory for Radiopharmacy-Faculty of Pharmaceutical Sciences, Department of Nuclear Medicine, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
Deroose
Christophe M
CM
Balzarini
Jan
J
Gijsbers
Rik
R
Celen
Sofie
S
Debyser
Zeger
Z
Mortelmans
Luc
L
Verbruggen
Alfons M
AM
Bormans
Guy M
GM
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002250:Carbon Radioisotopes; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D017930:Genes, Reporter; D014645:Herpesvirus 3, Human / Q000201:enzymology*; D006801:Humans; D008297:Male; D051379:Mice; D010766:Phosphorylation; D049268:Positron-Emission Tomography; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000235:genetics; D014018:Tissue Distribution
C527722:3-(2'-deoxyribofuranosyl)-6-(4-(1-fluoroethoxy)phenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2(3H)-one; C527721:3-(2'-deoxyribofuranosyl)-6-(4-methoxyphenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2(3H)-one; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D011741:Pyrimidine Nucleosides; D019275:Radiopharmaceuticals; D013937:Thymidine Kinase