We have prepared and tested radioligand [F]ONO-8430506 ([F]8) as a novel ATX PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. Radioligand [F]8 could be prepared in good and reproducible radiochemical yields of 35 ± 5% (n = 6) using late-stage radiofluorination chemistry. ATX binding analysis showed that 9-benzyl tetrahydro-b-carboline 8 has about five times better inhibitory potency than clinical candidate GLPG1690 and somewhat less inhibitory potency than ATX inhibitor PRIMATX. The binding mode for compound 8 inside the catalytic pocket of ATX using computational modelling and docking protocols revealed that compound 8 resembled a comparable binding mode to that of ATX inhibitor GLPG1690. However, PET imaging studies with radioligand [F]8 showed only relatively low tumour uptake and retention (SUV 0.21 ± 0.03) in the tested 8305C human thyroid tumour model reaching a tumour-to-muscle ratio of ∼ 2.2 after 60 min.
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