Comparison of [18F]FHPG and [124/125I]FIAU for imaging herpes simplex virus type 1 thymidine kinase gene expression

Various radiotracers based on uracil nucleosides (e,g, [I-124]2 ' -fluoro-2 ' -deoxy-5-iodo-1-beta -D-arabinofuranosyluracil, [I-124]FIAU) and acycloguanosine derivatives (e.g. [F-18]9-[(3-fluoro-1-hydroxy-2-propoxy)methyl] guanine, [F-18]FHPG) have been proposed for the non-invasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. However, these radiotracers have been evaluated in different in vitro and in vivo models, precluding a direct comparison. Therefore, we directly compared [F-18]FHPG and radioiodinated FIAU to assess their potential for PET imaging of transgene expression. The uptake of [I-125]FIAU, [F-18]FHPG and [H-3]acyclovir was determined in vitro using four different HSV1-tk expressing cell lines and their respective negative controls. The in vitro tracer uptake was generally low in non-transduced parental cell lines, In HSV1-tk expressing cells, [H-3]acyclovir showed approximately a twofold higher tracer accumulation, the [F-18]FHPG uptake increased by about sixfold and the ["SI]FIAU accumulation increased by about 28-fold after 120-min incubation of T1115 human glioblastoma cells. Similar results were found in the other cell lines, In addition, biodistribution and positron emission tomography (PET) studies with [F-18]FHPG and [I-124/125]FIAU were carried out in tumour-bearing BALB/c mice. Significantly higher specific accumulation of radioactivity was found for [I-125]FIAU compared with [F-18]FHPG. The ratio of specific tracer accumulation between [I-125]FIAU and [F-18]FHPG increased from 21 (30 min p.i.) to 119 (4 h p.i.), PET imaging, using [I-124]FIAU, clearly visualised and delineated HSV1-rk expressing tumours, whereas only a negligible uptake of [F-18]FHPG was observed, This study demonstrated that in vitro and in vivo, the radioiodinated uracil nucleoside FIAU has a significantly higher specific accumulation than the acycloguanosine derivative [F-18]FHPG. This suggests that [I-124]FIAU should be the preferred reporter probe for PET imaging of HSV1-tk gene expression, Thus, further attempts to develop suitable PET tracers for the assessment of HSV1-tk gene expression should also focus on F-18-labelled uracil derivatives.