Synthesis and in vitro evaluation of 5-[(18)f]fluoroalkyl pyrimidine nucleosides for molecular imaging of herpes simplex virus type 1 thymidine kinase reporter gene expression.
Two novel series of 5-fluoroalkyl-2'-deoxyuridines (FPrDU, FBuDU, FPeDU) and 2'-fluoro-2'-deoxy-5-fluoroalkylarabinouridines (FFPrAU, FFBuAU, FFPeAU) that have three, four, or five methylene units (propyl, butyl, or pentyl) at C-5 were prepared and tested as reporter probes for imaging herpes simplex virus type 1 thymidine kinase (HSV1- tk) gene expression. The Negishi coupling methodology was employed in efficiently synthesizing the radiolabeling precursors. All six 5-[(18)F]fluoroalkyl pyrimidines were readily prepared from 3-N-benzoyl-3',5'-di-O-benzoyl-protected 5-O-mesylate precursors in 17-35% radiochemical yield (decay-corrected). In vitro studies highlighted that all six [(18)F]-labeled nucleosides selectively accumulated in cells expressing the HSV1-TK protein and there was negligible uptake in control cells. [(18)F]FPrDU, [(18)F]FBuDU, [(18)F]FPeDU, and [(18)F]FFBuAU had the best uptake profiles. Despite their selective accumulation in HSV1- tk-expressing cells, all 5-fluoroalkyl pyrimidine nucleosides had low-to-negligible cytotoxic activity (CC50 > 1000-1209 microM). Ultimately, the results demonstrated that 5-[(18)F]fluoropropyl, [(18)F]fluorobutyl, and [(18)F]fluoropentyl pyrimidine nucleosides have the potential to be in vivo HSV1-TK PET reporter probes over a dynamic range of reporter gene expression levels.
Chacko
Ann-Marie
AM
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Qu
Wenchao
W
Kung
Hank F
HF
D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D017930:Genes, Reporter; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D049268:Positron-Emission Tomography; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000235:genetics*
D011741:Pyrimidine Nucleosides; D013937:Thymidine Kinase
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