Radiolabelling and PET evaluation of the PDE10A PET radioligands, [11C]T-773, [11C]KIT-5 and [11C]KIT-7 in nonhuman primates (NHP)

Objectives Phosphodiesterase 10A (PDE10A) inhibitors have been considered as potential drug candidates for several neuropsychiatric disorders. We radiolabeled three potential PET radioligands for PDE10A, [11C]T-773(=[11C]KIT-6) (IC50 = 0.36 nM) , [11C]KIT-5 (0.5 nM), [11C]KIT-7 (0.15 nM), and to evaluate them with NHP PET.

Methods All three radioligands were radiolabelled from precursors by methylation reaction with [11C]MeOTf. Baseline PET measurements were performed in two monkeys for each radioligand. After evaluation of the initial data, PET measurements with [11C]T-773 were performed in displacement and pretreatment paradigm using MP-10, a selective PDE10A inhibitor. Total distribution volume (VT) was calculated with several compartment models using metabolite-corrected plasma input. PDE10A occupancy was calculated using the binding potential BPND, calculated as DVR-1 using the cerebellum as a reference region.

Results Peak whole brain uptake was high (3-5%ID) in [11C]T-773 and [11C]KIT-5 but low in [11C]KIT-7. High uptake was seen in the striatum for all three PET radioligands. The specific binding (putamen - cerebellum) peaked at 42 min for [11C]T-773 with no robust peak during 120 min for [11C]KIT-7 and in one monkey for [11C]KIT-5. Washout from the peak in the cerebellum was fastest for [11C]T-773. For [11C]T-773, uptake in the putamen was displaced by MP-10. VT was decreased by MP-10 in the striatum but not in the cerebellum. Estimated BPND was approximately 1.8 in the putamen. Estimated PDE10A occupancy was approximately 70% after pretreatment with 1.8 mg/kg of MP-10.

Conclusions This study demonstrated that among three evaluated compounds, [11C]T-773 is the most promising PET radioligand for PDE10A with favorable characteristics for in vivo NHP.