A human [¹¹C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor

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• 作者：Akihiro Takano^a ; ^{akihiro.takano@ki.se" class="auth_mail" title="E-mail the corresponding author} ; Per Stenkrona^a ; Vladimir Stepanov^a ; Nahid Amini^a ; Stefan Martinsson^a ; Max Tsai^b ; Paul Goldsmith^c ; Jinhui Xie^b ; Jingtao Wu^b ; Tolga Uz^b ; Christer Halldin^a ; Thomas A. Macek^b
• 刊名：NeuroImage
• 出版年：2016
• 出版时间：1 November 2016
• 年：2016
• 卷：141
• 期：Complete
• 页码：10-17
• 全文大小：808 K

文摘

Phosphodiesterase 10A (PDE10A) is selectively expressed in the striatal regions in the brain and may play a role in modulating dopaminergic and glutamatergic second messenger pathways. PDE10A inhibitors are expected to be useful in treating neuropsychiatric disorders such as schizophrenia and Huntington’s disease. In this study, the brain kinetics of [¹¹C]T-773 in the human brain and test-retest reproducibility of the outcome measures were evaluated. Subsequently, the occupancy of a novel PDE10A inhibitor, TAK-063, was measured using [¹¹C]T-773.

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 (V_T), which was calculated as the V_T of the putamen minus the V_T 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 V_T was 5.5 ± 0.7 in the putamen and 2.3 ± 0.5 in the cerebellum in the baseline PET. Absolute V_T variability between the two baseline scans was less than 7%. Reproducibility of V_T 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.