Synthesis and biological characterisation of (18)F-SIG343 and (18)F-SIG353, novel and high selectivity σ(2) radiotracers, for tumour imaging properties

BACKGROUND: Sigma2 (σ(2)) receptors are highly expressed in cancer cell lines and in tumours. Two novel selective (18)F-phthalimido σ(2) ligands, (18)F-SIG343 and (18)F-SIG353, were prepared and characterised for their potential tumour imaging properties. METHODS: Preparation of (18)F-SIG343 and (18)F-SIG353 was achieved via nucleophilic substitution of their respective nitro precursors. In vitro studies including radioreceptor binding assays in the rat brain membrane and cell uptake studies in the A375 cell line were performed. In vivo studies were carried out in mice bearing A375 tumours including positron emission tomography (PET) imaging, biodistribution, blocking and metabolite studies. RESULTS: In vitro studies showed that SIG343 and SIG353 displayed excellent affinity and selectivity for σ(2) receptors (Ki(σ(2)) = 8 and 3 nM, σ(2):σ(1) = 200- and 110-fold, respectively). The σ(2) selectivity of (18)F-SIG343 was further confirmed by blocking studies in A375 cells, however, not noted for (18)F-SIG353. Biodistribution studies showed that both radiotracers had similar characteristics including moderately high tumour uptake (4%ID/g to 5%ID/g); low bone uptake (3%ID/g to 4%ID/g); and high tumour-to-muscle uptake ratios (four- to sevenfold) up to 120 min. Although radiotracer uptake in organs known to express σ receptors was significantly blocked by pre-injection of competing σ ligands, the blocking effect was not observed in the tumour. PET imaging studies indicated major radioactive localisation in the chest cavity for both ligands, with approximately 1%ID/g uptake in the tumour at 120 min. Metabolite studies showed that the original radiotracers remained unchanged 65% to 80% in the tumour up to 120 min. CONCLUSIONS: The lead ligands showed promising in vitro and in vivo characteristics. However, PET imaging indicated low tumour-to-background ratios. Furthermore, we were unable to demonstrate that uptake in the A375 tumour was σ(2)-specific. (18)F-SIG343 and (18)F-SIG343 do not display ideal properties for imaging the σ(2) receptor in the A375 tumour model. However, since the radiotracers show promising in vitro and in vivo characteristics, longer scans using appropriate half-life isotopes and alternative tumour models will be carried out in future studies to fully validate the imaging characteristics of these radiotracers.