Imaging of HSV-tk Reporter Gene Expression: Comparison Between [18F]FEAU, [18F]FFEAU, and Other Imaging Probes

Herpes virus type 1 thymidine kinase (HSV1 -tk) and the mutant HSV1 -sr39tk are the 2 most widely used "reporter genes" for radiotracer-based imaging. Two pyrimidine nucleoside analogs, [ 18 F]FEAU (1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-5-ethyl-uridine) and [ 18 F]FFEAU (1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-5-(2-fluoroethyl)uridine), have generated recent interest as potential new probes for imaging HSV1 -tk and HSV1 -sr39tk gene expression. Methods: We compared [ 18 F]FEAU and [ 18 F]FFEAU with a series of other pyrimidine nucleoside derivatives (including 1-(2'-deoxy-2'-fluoro-β-D-arabinofuranosyl)-5-iodouridine [FIAU]) and with acycloguanosine analogs using a stable HSV1-tk transduced cell line (RG2TK+) and wild-type RG2 cells. Results: The in vitro accumulation data and the calculated and normalized clearance constant, nKi, as well as sensitivity and selectivity indices indicated that 2 pyrimidine nucleoside probes, [ 18 F]FEAU and [ 18 F]FFEAU, had the best uptake characteristics. These probes were selected for further dynamic PET studies in nude rats bearing subcutaneous RG2TK+ and RG2 tumors. The 2-h postinjection [ 18 F]FEAU uptake levels were 3.3% ± 1.0% and 0.28% ± 0.07% dose/cm 3 in subcutaneous RG2TK+ and RG2 tumors, respectively, and 2.3% ± 0.2% and 0.19% ± 0.01% dose/cm 3 , respectively, for [ 18 F]FFEAU. The corresponding RG2TK+/RG2 uptake ratios were 11.5 ± 1.5 and 12.2 ± 1.4, respectively. The inherent problem of comparing different radiolabeled pyrimidine nucleoside and guanosine-based probes for imaging HSV1 -tk expression using different transduced cell lines and assay systems in the absence of an independent thymidine kinase-enzyme assay is discussed. Conclusion: For HSV1-tk reporter systems that require a 1- to 4-h PET paradigm, HSV1-tk-[ 18 F]FEAU is the current top contender.