Takano Akihiro, Stenkrona Per, Stepanov Vladimir, Amini Nahid, Martinsson Stefan, Tsai Max, Goldsmith Paul, Xie Jinhui, Wu Jingtao, Uz Tolga, Halldin Christer, Macek Thomas A
Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
Karolinska Institutet, Department of Clinical Neuroscience, Center for Psychiatric Research, Stockholm, Sweden.
Neuroimage. 2016 Nov 1;141:10-17. doi: 10.1016/j.neuroimage.2016.06.047. Epub 2016 Jul 15.
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 [(11)C]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 [(11)C]T-773. Dynamic PET measurements were conducted three times for 12 healthy male subjects after intravenous bolus injection of [(11)C]T-773: two baseline PETs and one postdose PET (3hours) after oral administration of TAK-063 for four subjects, and one baseline PET and two postdose PET (3hours and 23hours) 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 3hours after a single administration of 3 to 1000mg of TAK-063, and increased in a dose- and plasma concentration-dependent manner. At 23hours postdose, PDE10A occupancy in the putamen was 0 to 42.8% following administration of 3 to 100mg of TAK-063. In conclusion, [(11)C]T-773 showed good characteristics as a PET radioligand for PDE10A in the human brain.
磷酸二酯酶10A（PDE10A）在大脑的纹状体区域选择性表达，可能在调节多巴胺能和谷氨酸能第二信使途径中发挥作用。PDE10A抑制剂有望用于治疗精神分裂症和亨廷顿病等神经精神疾病。在本研究中，评估了[(11)C]T-773在人脑中的脑动力学以及结果测量的重测再现性。随后，使用[(11)C]T-773测量了新型PDE10A抑制剂TAK-063的占有率。对12名健康男性受试者静脉推注[(11)C]T-773后进行了三次动态PET测量：4名受试者口服TAK-063后进行两次基线PET扫描和一次给药后PET扫描（3小时），8名受试者进行一次基线PET扫描和两次给药后PET扫描（3小时和23小时）。采用动脉输入函数进行动力学模型分析。PDE10A占有率计算为PDE10A特异性结合（Vs）总分布容积（VT）的百分比变化，VT计算为壳核的VT减去小脑的VT。大脑区域摄取在壳核中最高。用双组织室（2TC）模型描述脑区的时间-活性曲线。基线PET扫描时，壳核的平均VT为5.5±0.7，小脑的平均VT为2.3±0.5。两次基线扫描之间的绝对VT变异性小于7%。VT的再现性极佳。单次给予3至1000mg TAK-063后3小时，壳核中的PDE10A占有率为2.8%至72.1%，并呈剂量和血浆浓度依赖性增加。给药后23小时，给予3至100mg TAK-063后，壳核中的PDE10A占有率为0至42.8%。总之，[(11)C]T-773作为人脑中PDE10A的PET放射性配体表现出良好的特性。
