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

Various radiotracers based on uracil nucleosides (e.g 2'-fluoro-2'-deoxy-5-[¹²⁴I]iodo-1-beta-D-arabinofuranosyluracil, [¹²⁴I]FIAU) and acycloguanosine derivatives (e.g. 9-[(3-[¹⁸F]fluoro-1-hydroxy-2-propoxy)methyl]guanine, [¹⁸F]FHPG) have been proposed as suitable substrates for the noninvasive imaging of herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene expression. However, for evaluation of these tracers different in vitro and in vivo models were used which did not permit a direct comparison of selectivity and affinity. Therefore, we directly compared [¹⁸F]FHPG and radioiodinated FIAU to assess their potential for PET imaging of transgene expression.
The uptake of [¹²⁵I]FIAU, [¹⁸F]FHPG and [³H]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 nontransduced cell lines demonstrating low affinity to cellular thymidine kinases. In HSV1-tk expressing cells, [³H]acyclovir showed approximately a 2-fold higher tracer accumulation, the [¹⁸F]FHPG uptake increased to approximately 6-fold and the [¹²⁵I]FIAU accumulation to approximately 28-fold after 120 min incubation of T1115 human glioblastoma cells. Similar results were found in the other cell lines. In addition, biodistribution and PET studies with [¹⁸F]FHPG and [^124/125I]FIAU were carried out in tumour-bearing BALB/c mice. Significantly higher specific tracer accumulation was found for [¹²⁵I]FIAU compared to [¹⁸F]FHPG. The ratio of specific tracer accumulation between [¹²⁵I]FIAU and [¹⁸F]FHPG increased from 21 (30 min p.i.) to 119 (4 hours p.i.). PET imaging, using [¹²⁴I]FIAU, clearly visualised and delineated HSV1-tk expressing tumours, whereas only a negligible uptake of [¹⁸F]FHPG was observed.
This study demonstrated that in vitro and in vivo, the radioiodine labelled uracil nucleoside FIAU has a significantly higher specific accumulation than the acycloguanosine derivative [¹⁸F]FHPG. This suggests that [¹²⁴I]FIAU should be the preferred reporter probe for PET imaging of HSV1-tk gene expression. However, the use of [¹²⁴I]FIAU is hampered by the relatively long physical half-life, the low positron emission and the limited availability of the radionuclide. Thus, further attempts to develop suitable PET tracers for the assessment of HSV1-tk gene expression should also focus on ¹⁸F-labelled uracil derivatives.