| Abstract: |
Rationale and Objectives. Introduction of suicide genes, such as herpes simplex virus type1 thymidine kinase (HSV1-tk), in tumor cells has provided a useful method for tumor gene therapy. Several L-nucleosides, such as Lamivudine (3TC) and Clevudine (L-FMAU), have been successfully tested as high-potency antiviral agents. To investigate the potential differences between D- and L-isomers of nucleosides, [ 125/123I]-2'-fluoro-2'-deoxy-1β-D/L- arabino-furanosy-5-iodo-uracil (D/L-FIAU) have been synthesized and evaluated as potential SPECT agents for imaging HSV1-tk gene expression. Materials and Methods. [ 125/123I]D- and L-FIAU were prepared by iododestannylation of the respective tin precursors with 125/123I-sodium iodide. In vitro cell uptake studies were performed by incubation of [ 125I]D- and L-FIAU in RG2 cells expressing HSV1-tk (RG2TK+). In vivo studies including biodistribution and SPECT were performed in RG2TK+ and RG2TK- tumor-bearing nude mice using [ 123I]D- and L-FIAU. Results. Cell uptake and biodistribution studies indicated that [ 125/123I]L-FIAU did not show any high accumulation (sensitivity) or uptake ratios (selectivity) in HSV1-TK-positive (RG2TK+) tumors as compared to control tumors. In contrast, [ 125/123I]D-FIAU displayed both sensitivity and selectivity to RG2TK+ tumors. The selective in vivo accumulation of [ 123I]D-FIAU increased with time and the tumor uptake ratios (RG2TK+/RG2TK-) for 2, 4, and 24 hours averaged 6.2, 22.7, and 58.8, respectively. High-resolution SPECT of four nude tumor-bearing mice demonstrated a very high uptake of [ 123I]D-FIAU in the RG2TK+ tumor, while no significant tracer accumulation was observed in the RG2TK- tumor and other organs. Conclusion. The data suggest that only the D-isomer of [ 123I]FIAU is useful for imaging HSV1-tk gene expression in mice by high-resolution SPECT imaging. © AUR, 2005. |
