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Synthesis and Evaluation of 2'-Deoxy-2'-¹⁸F-Fluoro-5-Fluoro-1-ß-D-Arabinofuranosyluracil as a Potential PET Imaging Agent for Suicide Gene Expression

PET Imaging Science Center, Department of Radiology, University of Southern California, Los Angeles, California

2'-Deoxy-2'-¹⁸F-fluoro-5-fluoro-1-ß-D-arabinofuranosyluracil (¹⁸F-FFAU) has been synthesized and evaluated in HT-29 cells as a potential PET agent for herpes simplex virus type 1 thymidine kinase (HSV1-tk) gene expression. Methods: 2-Deoxy-2-¹⁸F-fluoro-1,3,5-tri-O-benzoyl--D-arabinofuranose was prepared by the reaction of the respective 2-triflate with tetrabutylammonium ¹⁸F-fluoride. The fluorosugar was converted to its 1-bromo derivative and coupled with protected 5-fluorouracil. The crude product was hydrolyzed in base and purified by high-performance liquid chromatography to obtain the ¹⁸F-FFAU. In vitro studies were performed in HT-29 cells by incubation at various time points. In vivo studies including biodistribution and microPET were performed in tumor-bearing nude mice. Results: The radiochemical yield was 20%–30% decay corrected with an average of 25% in 4 runs. Radiochemical purity was >99% and average specific activity was 85 GBq/µmol (2,300 mCi/µmol) (end of synthesis). In vitro accumulation of ³H-FFAU in HSV1-tk–expressing cells was 180-fold (P < 0.001) higher than that in the wild-type cells between 30 and 120 min. In vivo uptake of ³H-FFAU in HSV1-tk–positive tumors at 2 h was 8-fold (P < 0.001) higher than that in the control tumors. Tumor uptake (percentage injected dose per gram of tissue) and the uptake ratio (tk-positive to wild type) of ³H-FFAU in tk-positive cells was higher compared with those of our earlier studies using 2'-¹⁴C-deoxy-2'-fluoro-5-methyl-1-ß-D-arabinofuranosyluracil (¹⁴C-FMAU) and 9-(4-¹⁸F-fluoro-3-hydroxymethylbutyl)guanine (¹⁸F-FHBG) in the same cell lines. microPET on tumor-bearing nude mice also demonstrated a very high uptake of ¹⁸F-FFAU in tk-positive tumors compared with that of the control tumor without significant accumulation in other organs. Conclusion: These results demonstrate that ¹⁸F-FFAU has superior biodistribution characteristics and significantly higher in vivo uptake in HSV1-tk–expressing tumor compared with previously studied agents.

Key Words: 2'-deoxy-2'-¹⁸F-fluoro-5-fluoro-1-ß-D-arabinofuranosyluracil • herpes simplex virus type-1 thymidine kinase • HT-29 cells • PET • gene expression

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