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Comparison of [18F]FHBG and [14C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection

  • Molecular Imaging
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Earlier studies involving comparison of different reporter probes have shown conflicting results between pyrimidine nucleosides [e.g., 2'-fluoro-2'-deoxy-1-β-d-arabinofuranosyl-5-iodouracil (FIAU)] and acycloguanosine derivatives [e.g., penciclovir (PCV), 9-(4-fluoro-3-hydroxymethylbutyl)guanine (FHBG)]. We hypothesized that this reported discrepancy may be related to how the reporter gene is delivered to the cells—stably transfected vs adenoviral infection. We directly compared the uptake characteristics of [18F]FHBG, [3H]PCV, and [14C]FIAU in cell culture and in vivo using an adenoviral mediated gene transfer model and stably transfected cells. We further compared the uptake of three reporter probes using both HSV1-tk and a mutant HSV1-sr39tk expressing cells to assess the optimal reporter probe/reporter gene combination. [14C]FIAU accumulation was greater than that of [3H]PCV and [18F]FHBG in control cells and in HSV1-tk stably transfected cells (P<0.001). After infection of C6 cells with AdCMV-HSV1-tk (1.5×108 pfu), [18F]FHBG and [3H]PCV accumulation was significantly greater than that of [14C]FIAU (P<0.01). [18F]FHBG and [3H]PCV accumulated to a significantly greater extent than [14C]FIAU in C6-stb-sr39tk+ and AdCMV-HSV1-sr39tk infected C6 cells (P<0.001). Results from the nude mice supported the results in cell culture. [14C]FIAU led to significantly higher %ID/g in C6-stb-tk+ xenografts than [18F]FHBG (P<0.05); however, compared with [14C]FIAU, [18F]FHBG led to as high %ID/g in HSV1-tk expressing hepatocytes and to significantly greater %ID/g in C6-stb-sr39tk+ xenografts and HSV1-sr39tk expressing hepatocytes. Dynamic sequential images showed that [18F]FHBG was well retained in HSV1-sr39tk expressing cells (C6-stb-sr39tk+) for at least 4 h after injection, while it was rapidly cleared from HSV1-tk expressing cells (MH3924A-stb-tk+). [14C]FIAU accumulated in HSV1-tk stably expressing cells to a greater extent than either [3H]PCV or [18F]FHBG. However, the accumulation of [3H]PCV and [18F]FHBG in adenoviral infected C6 cells or hepatocytes was equivalent to or greater than that of [14C]FIAU. These results may be due to intracellular biochemical changes (e.g., thymidine) when cells are infected with adenovirus. For adenoviral studies, the [18F]FHBG/HSV1-sr39tk combination was shown to be more sensitive than the [14C]FIAU/HSV1-tk combination HSV1-tk.

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Acknowledgements

We thank Drs. D. Stout, W. Ladno, J. Edwards, X.Z. Lewis, F. Berger, and G. Sundaresan for their technical assistance. This work was supported in part by National Institutes of Health Grants P50 CA86306, R0-1 CA82214, Small Animal Imaging Resource Program R24 CA92865, and Department of Energy Contract DE-FC03-87ER60615 (all to S.S.G.).

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Authors and Affiliations

  1. The Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, B3-399A BRI 700 Westwood Plaza, Los Angeles, CA 90095-1770, USA

    Jung-Jun Min, Meera Iyer & Sanjiv S. Gambhir

  2. Department of Radiology, Bio-X Program, Stanford University, Stanford, California, USA

    Sanjiv S. Gambhir

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Correspondence to Sanjiv S. Gambhir.

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Min, JJ., Iyer, M. & Gambhir, S.S. Comparison of [18F]FHBG and [14C]FIAU for imaging of HSV1-tk reporter gene expression: adenoviral infection vs stable transfection. Eur J Nucl Med Mol Imaging 30, 1547–1560 (2003). https://doi.org/10.1007/s00259-003-1238-6

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