5-[¹⁸F]Fluoroalkyl pyrimidine nucleosides: probes for positron emission tomography imaging of herpes simplex virus type 1 thymidine kinase gene expression☆

Abstract 

Introduction

The preliminary in vivo evaluation of novel 5-[¹⁸F]fluoroalkyl-2′-deoxyuridines ([¹⁸F]FPrDU, [¹⁸F]FBuDU, [¹⁸F]FPeDU; [¹⁸F]1a−c, respectively) and 2′-fluoro-2′-deoxy-5-[¹⁸F]fluoroalkyl-1-β-d-arabinofuranosyl uracils ([¹⁸F]FFPrAU, [¹⁸F]FFBuAU, [¹⁸F]FFPeAU; [¹⁸F]1d−f, respectively) as probes for imaging herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression is described.

Methods

[¹⁸F]1a−f were successfully synthesized by a rapid and efficient two-step one-pot nucleophilic fluorination reaction using 5-O-mesylate precursors and [¹⁸F]F⁻. For in vivo studies, tumor xenografts were grown in nude mice by implanting RG2 cells stably expressing HSV1-tk (RG2TK+) and wild-type cells (RG2).

Results

Biodistribution studies at 2 h pi revealed that the uptake of [¹⁸F]1a−b and [¹⁸F]1d−e in RG2TK+ tumors was not significantly different from control tumors. However, [¹⁸F]1c and [¹⁸F]1f had an average 1.6- and 1.7-fold higher uptake in RG2TK+ tumors than control RG2 tumors. Blood activity curves for [¹⁸F]1c and [¹⁸F]1f highlight rapid clearance of radioactivity in the blood. Dynamic small animal PET (A-PET) imaging studies of tumor-bearing mice with [¹⁸F]1c and [¹⁸F]1f showed higher initial uptake (3.5- and 1.4-fold, respectively) in RG2TK+ tumors than in control tumors, with continued washout of activity from both tumors over time.

Conclusions

Biological evaluations suggest that [¹⁸F]1c and [¹⁸F]1f may have limited potential for imaging HSV1-tk gene expression due to fast washout of activity from the blood, thus significantly decreasing sensitivity and specificity of tracer accumulation in HSV1-tk-expressing tumors.

Keywords: 5-[¹⁸F]Fluoroalkyl pyrimidine nucleosides, HSV1-tk, PET, Reporter gene imaging