Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [11C]T-773: two baseline PETs and one postdose PET (3 hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3 hours and 23 hours) for eight subjects. Kinetic model analysis was performed with arterial input functions. PDE10A occupancy was calculated as the percent change of the binding specific to PDE10A (Vs) total distribution volume (VT), which was calculated as the VT of the putamen minus the VT of the cerebellum.
Regional brain uptake was highest in the putamen. Time-activity curves of the brain regions were described with two tissue-compartment (2TC) models. The mean VT was 5.5 ± 0.7 in the putamen and 2.3 ± 0.5 in the cerebellum in the baseline PET. Absolute VT variability between the two baseline scans was less than 7%. Reproducibility of VT was excellent. PDE10A occupancy in the putamen ranged from 2.8% to 72.1% at 3 hours after a single administration of 3 to 1000 mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23 hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100 mg of TAK-063. In conclusion, [11C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.