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


METHODS
[(18)F]1a-f were successfully synthesized by a rapid and efficient two-step one-pot nucleophilic fluorination reaction using 5-O-mesylate precursors and [(18)F]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 [(18)F]1a-b and [(18)F]1d-e in RG2TK+ tumors was not significantly different from control tumors. However, [(18)F]1c and [(18)F]1f had an average 1.6- and 1.7-fold higher uptake in RG2TK+ tumors than control RG2 tumors. Blood activity curves for [(18)F]1c and [(18)F]1f highlight rapid clearance of radioactivity in the blood. Dynamic small animal PET (A-PET) imaging studies of tumor-bearing mice with [(18)F]1c and [(18)F]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 [(18)F]1c and [(18)F]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.
Chacko
Ann-Marie
AM
Institute for Environmental Medicine, Targeted Therapeutics Program, University of Pennsylvania, Philadelphia, PA 19104, USA.
Blankemeyer
Eric
E
Lieberman
Brian P
BP
Qu
Wenchao
W
Kung
Hank F
HF
D000818:Animals; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D015870:Gene Expression; D017930:Genes, Reporter / Q000235:genetics*; D005910:Glioma / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D011741:Pyrimidine Nucleosides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013937:Thymidine Kinase / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics*; D013997:Time Factors; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D005462:Fluorine Radioisotopes; D011741:Pyrimidine Nucleosides; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase