8-[F-18]fluoropenciclovir: An improved reporter probe for imaging HSV1-tk reporter gene expression in vivo using PET

We have synthesized and evaluated 8-[F-18]fluoropenciclovir (FPCV) and comp ared it with 8-[F-18]fluoroganciclovir (FGCV) for monitoring the expression of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene in cell culture and in vivo. Methods: C6 rat glioma cells stably transfected with HSV1-tk (CG-stb-tk+) and control C6 cells were evaluated for their abi lity to accumulate FGCV versus FPCV. For in vivo studies, 15 mice were inje cted by tail vein with increasing levels of an adenoviral Vector carrying H SV1-tk. Forty-eight hours later the mice were injected with FPCV and killed 3 h later. The percentage injected dose per gram (%ID/g) liver was then de termined. Two additional mice were studied by microPET and autoradiography using FPGV to image adenoviral-mediated hepatic HSV1-tk reporter gene expre ssion. A tumor-bearing mouse (C6 control and CG-stb-tk+) was imaged with FD G, FGCV, and FPCV. Two mice carrying tumors expressing two different report er genes, HSV1-tk and dopamine type 2 receptor (D2R), were also imaged by m icroPET using FPCV (day 1) and 3-(2'-[F-18]fluoroethyl)spiperone (FESP) (da y 2). Results: FPCV shows a significantly greater accumulation in CG-stb-tk + cells than does FGCV (P < 0.05). Over identical ranges of adenoviral admi nistration, mouse liver shows a higher %ID/g liver for FPCV (0%-9%) compare d with our previously reported results with FGCV (0%-3%). In C6 control and CG6-stb-tk+ tumor-bearing mice, FPCV has a greater accumulation than does FGCV for equal levels of HSV1-tk gene expression. In mice carrying tumors e xpressing either HSV1-tk or D2R reporter genes, there is a corresponding re tention of FPGV and FESP, respectively. Conclusion: These results indicate that FPCV is a better reporter probe than is FGCV for imaging lower levels of HSV1-tk gene expression in vivo. The results also reveal the ability to monitor the expression of two distinct reporter genes in the same animal us ing reporter probes specific for each gene.