Favourable pharmacokinetics of the
prodrug are essential for successful HSVtk/
ganciclovir (GCV) suicide gene therapy. [(
18)F]FHPG PET might be a suitable technique to assess the pharmacokinetics of the
prodrug GCV noninvasively, provided that [(
18)F]FHPG mimics the behaviour of GCV. Since membrane transport is an important aspect of the pharmacokinetics of the
prodrug, we investigated the cellular uptake mechanism of [(
18)F]FHPG in an HSVtk expressing C6 rat
glioma cell line and in tumour-bearing rats. The
nucleoside transport inhibitors dipyridamol,
NBMPR and
2-chloroadenosine did not significantly affect the [(
18)F]FHPG uptake in vitro.
Thymidine and
uridine significantly decreased [(
18)F]FHPG uptake by 84 and 58%, respectively, but an
enzyme assay revealed that this decline was due to inhibition of the HSVtk
enzyme rather than membrane transport. Nucleobase transport inhibitors,
thymine and
adenine, caused a 58 and 55% decline in tracer uptake, respectively. In vivo, the ratio of [(
18)F]FHPG uptake in C6tk and C6 tumours decreased from 3.0+/-0.5 to 1.0+/-0.2 after infusion of
adenine. Thus, in our tumour model, [(
18)F]FHPG transport exclusively occurred via
purine nucleobase transport. In this respect, FHPG does not resemble GCV, which is predominantly taken up via the
nucleoside transporter, but rather
acyclovir, which is also taken up via the
purine nucleobase carrier.