Brain PET measurement of PDE10A occupancy by TAK-063, a new PDE10A inhibitor, using [11 C]T-773 in nonhuman primates

Akihiro Takano, Vladimir Stepanov, Ryuji Nakao, Nahid Amini, Balázs Gulyás, Haruhide Kimura, Christer Halldin
Synapse 2016, 70 (6): 253-63
Because phosphodiesterase 10A (PDE10A) degrades both cyclic adenosine monophosphate and cyclic guanosine monophosphate and is distributed mainly in the striatum, PDE10A inhibitors have been considered to potentially be useful therapeutic agents for psychiatric and neurodegenerative diseases such as schizophrenia and Huntington's disease. We measured striatal PDE10A occupancy by TAK-063, a newly developed compound with high affinity and selectivity for PDE10A, using PET with [(11)C]T-773 in nonhuman primates. Two 123-min dynamic PET measurements were performed on three female rhesus monkeys, once at baseline and again after intravenous administration of different doses of TAK-063 (0.2-1.6 mg/kg). Total distribution volume (V(T)) was calculated with a two-tissue compartment model using metabolite-corrected plasma input. Although the in vitro autoradiography did not show high specific binding to [(11)C]T-773 in the cerebellum, V(T) in the cerebellum decreased after TAK-063 treatment. The specific binding to PDE10A (V(S)) was calculated as the difference of the V(T) between the target regions and the cerebellum. PDE10A occupancy was calculated as the percent change of V(S). The average PDE10A occupancy of the caudate nucleus and putamen was 35.2% at 0.2 mg/kg and 83.2% at 1.6 mg/kg. In conclusion, this nonhuman primate PET study demonstrated that [(11)C]T-773 is useful to estimate the PDE10A occupancy by TAK-063 in the striatum although there is in vivo interaction of the uptake between [(11)C]T-773 and TAK-063 in the cerebellum. These results warrant further clinical occupancy study for TAK-063.

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