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

¹ Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York
² Radiochemistry/Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
³ Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York; Radiochemistry/Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York
⁴ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York
⁵ Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York; Radiochemistry/Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
⁶ Radiochemistry/Cyclotron Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York
⁷ Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York

^* To whom correspondence should be addressed. E-mail: Blasberg{at}neuro1.mskcc.org.

	Abstract

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, [¹⁸F]FEAU (1-(2'-deoxy-2'-fluoro--D-arabinofuranosyl)-5-ethyluridine) and [¹⁸F]FFEAU (1-(2'-deoxy-2'-fluoro--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 [¹⁸F]FEAU and [¹⁸F]FFEAU with a series of other pyrimidine nucleoside derivatives (including 1-(2'-deoxy-2'-fluoro--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, [¹⁸F]FEAU and [¹⁸F]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 [¹⁸F]FEAU uptake levels were 3.3% ± 1.0% and 0.28% ± 0.07% dose/cm³ in subcutaneous RG2TK+ and RG2 tumors, respectively, and 2.3% ± 0.2% and 0.19% ± 0.01% dose/cm³, respectively, for [¹⁸F]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-[¹⁸F]FEAU is the current top contender.

Key Words: HSV1-tk, herpes simplex virus type 1 thymidine kinase, PET, FEAU, FFEAU, FIAU, ¹⁸F, reporter gene

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