Herpes simplex virus thymidine kinase imaging in mice with (1-(2′-deoxy-2′-[¹⁸F]fluoro-1-β-D-arabinofuranosyl)- 5-iodouracil) and metabolite (1-(2′-deoxy-2′-[¹⁸F]fluoro- 1-β-D-arabinofuranosyl)-5-uracil)

Purpose: FIAU, (1-(2′-deoxy-2′-fluoro-1-β-D- arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of ¹⁸F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of ¹⁸F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite ¹⁸F-FAU. Methods: CD-1 nu/nu mice with subcutaneous MH3924A and MH3924A-stb-tk+ xenografts on opposite flanks were used for the biodistribution and imaging studies. Mice were injected IV with either ¹⁸F-FIAU or ¹⁸F-FAU. Mice underwent dynamic imaging with each tracer for 65 min followed by additional static imaging up to 150 min post-injection for some animals. Animals were sacrificed at 60 or 150 min post-injection. Samples of blood and tissue were collected for biodistribution and metabolite analysis. Regions of interest were drawn over the images obtained from both tumors to calculate the time-activity curves. Results: Biodistribution and imaging studies showed the highest uptake of ¹⁸F-FIAU in the MH3924A-stb-tk+ tumors. Dynamic imaging studies revealed a continuous accumulation of ¹⁸F-FIAU in HSV-TK expressing tumors over 60 min. The mean biodistribution values (SUV ± SE) for MH3924A-stb-tk+ were 2.07±0.40 and 6.15±1.58 and that of MH3924A tumors were 0.19±0.07 and 0.47±0.06 at 60 and 150 min, respectively. In ¹⁸F-FIAU injected mice, at 60 min nearly 63% of blood activity was present as its metabolite ¹⁸F-FAU. Imaging and biodistribution studies with ¹⁸F-FAU demonstrated no specific accumulation in MH3924A-stb-tk+ tumors and SUVs for both the tumors were similar to those observed with muscle. Conclusion: ¹⁸F-FIAU shows a continuous accumulation of activity in HSV-TK expressing tumors. ¹⁸F-FAU does not show any preferential accumulation in HSV-TK expressing tumors. In the ¹⁸F-FIAU treated mice, the ¹⁸F-FAU contribution to the total uptake seen in HSV-TK positive tumors is minimal.