Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacokinetics
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Carbon Radioisotopes
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Cell Line
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Chromatography, High Pressure Liquid
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Fluorine Radioisotopes*
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Genes, Reporter
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Herpesvirus 3, Human / enzymology*
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Humans
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Male
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Mice
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Phosphorylation
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Positron-Emission Tomography
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Pyrimidine Nucleosides / chemical synthesis*
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Pyrimidine Nucleosides / pharmacokinetics
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Pyrimidine Nucleosides / pharmacology
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Radiopharmaceuticals / chemical synthesis*
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Radiopharmaceuticals / pharmacokinetics
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Radiopharmaceuticals / pharmacology
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Structure-Activity Relationship
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Thymidine Kinase / biosynthesis*
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Thymidine Kinase / genetics
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Tissue Distribution
Substances
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3-(2'-deoxyribofuranosyl)-6-(4-(1-fluoroethoxy)phenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2(3H)-one
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3-(2'-deoxyribofuranosyl)-6-(4-methoxyphenyl)-2,3-dihydrofuro(2,3-d)pyrimidin-2(3H)-one
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Bridged Bicyclo Compounds, Heterocyclic
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Carbon Radioisotopes
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Fluorine Radioisotopes
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Pyrimidine Nucleosides
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Radiopharmaceuticals
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Thymidine Kinase