Imaging of HSV-tk Reporter Gene Expression: Comparison Between [18F]FEAU, [18F]FFEAU, and Other Imaging Probes
Tadashi Miyagawa 1,
George Gogiberidze 1,
Inna Serganova 1,
Shangde Cai 2,
Julius A. Balatoni 3,
Howard T. Thaler 4,
Lyudmila Ageyeva 1,
Nagavarakishore Pillarsetty 5,
Ronald D. Finn 6,
and
Ronald G. Blasberg 7*
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.
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Abstract |
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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
