Synthesis and evaluation of 2'-deoxy-2'-18F-fluoro-5-fluoro-1-beta-D-arabinofuranosyluracil as a potential PET imaging agent for suicide gene expression.

Abstract

UNLABELLED:

2'-deoxy-2'-(18)F-fluoro-5-fluoro-1-beta-D-arabinofuranosyluracil ((18)F-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-(18)F-fluoro-1,3,5-tri-O-benzoyl-alpha-D-arabinofuranose was prepared by the reaction of the respective 2-triflate with tetrabutylammonium (18)F-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 (18)F-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/micromol (2,300 mCi/micromol) (end of synthesis). In vitro accumulation of (3)H-FFAU in HSV1-tk-expressing cells was approximately 180-fold (P < 0.001) higher than that in the wild-type cells between 30 and 120 min. In vivo uptake of (3)H-FFAU in HSV1-tk-positive tumors at 2 h was approximately 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 (3)H-FFAU in tk-positive cells was higher compared with those of our earlier studies using 2'-(14)C-deoxy-2'-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil ((14)C-FMAU) and 9-(4-(18)F-fluoro-3-hydroxymethylbutyl)guanine ((18)F-FHBG) in the same cell lines. microPET on tumor-bearing nude mice also demonstrated a very high uptake of (18)F-FFAU in tk-positive tumors compared with that of the control tumor without significant accumulation in other organs.

CONCLUSION:

These results demonstrate that (18)F-FFAU has superior biodistribution characteristics and significantly higher in vivo uptake in HSV1-tk-expressing tumor compared with previously studied agents.

• Authors: Mian M Alauddin, Antranic Shahinian, Ryan Park, Michel Tohme, John D Fissekis, Peter S Conti
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 45 Issue 12 Pg. 2063-9 (Dec 2004) ISSN: 0161-5505 [Print] United States
• PMID: 15585483 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2'-deoxy-2'-18F-fluoro-5-fluoro-1-beta-D-arabinofuranosyluracil
• Fluorine Radioisotopes
• Arabinofuranosyluracil
• Thymidine Kinase
• Fluorouracil

Topics

• Animals
• Arabinofuranosyluracil (analogs & derivatives, chemical synthesis)
• Fluorine Radioisotopes (pharmacokinetics)
• Fluorouracil (analogs & derivatives, chemical synthesis)
• Gene Expression
• HT29 Cells
• Herpesvirus 1, Human (enzymology)
• Humans
• Mice
• Positron-Emission Tomography (methods)
• Thymidine Kinase (metabolism)