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

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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 (PHSV1-tk (1.5×108 pfu), [18F]FHBG and [3H]PCV accumulation was significantly greater than that of [14C]FIAU (P18F]FHBG and [3H]PCV accumulated to a significantly greater extent than [14C]FIAU in C6-stb-sr39tk+ and AdCMV-HSV1-sr39tk infected C6 cells (P14C]FIAU led to significantly higher %ID/g in C6-stb-tk+ xenografts than [18F]FHBG (P14C]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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