In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects
In vivo measurement of PDE10A enzyme occupancy by positron emission tomography (PET) following single oral dose administration of PF-02545920 in healthy male subjects
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DOI：
10.1016/j.neuropharm.2017.01.016
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发表时间：
2017-05-01
影响因子：
4.7
通讯作者：
Varrone, Andrea
中科院分区：
文献类型：
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作者：
Delnomdedieu, Marielle;Forsberg, Anton;Varrone, Andrea
磷酸二酯酶 10A (PDE10A) 是一种在纹状体中型多棘神经元中高度富集的酶。它参与 cAMP 和 cGMP 细胞质水平的调节以及基底神经节内的信号传导。这项使用 PDE10A 放射性配体 [F-18]MNI-659 的研究旨在测量 8 名健康男性志愿者（48 +/- 4 岁）单次口服剂量（10 mg 或 20 mg）后 PF-02545920 的酶占用率，并评估安全性和耐受性。进行动脉血采样以获得代谢物校正的血浆输入函数，用于定量[ 18 F]MNI-659与PDE10A的结合。 PF-02545920 的占据率通过两种不同的方法计算：在方法 1 中，[18F]MNI-659 酶占据率是根据结合电位的估计值计算的，使用小脑作为参考区域；在方法 2 中，占用率是根据修正后的拉森图的斜率估算的。测量 PF-02545920 的血清浓度以确定浓度和占用率之间的关系。根据方法 1，纹状体 PDE10A 占有率随着 PF-02545920 剂量的增加而增加：10 mg 剂量时为 14-27% (N = 4)，20 mg 剂量时为 45-63% (N = 3)。使用拉森图方法 2 观察到可比较的占用率：10 mg：14-37%； 20 毫克：46-55%。使用 Emax 模型可以最好地描述暴露量和占用率之间的关系。与 50% 占有率相关的血清浓度估计为 93.2 ng/mL。单次口服 10 mg 或 20 mg PF-02545920 在健康男性志愿者中是安全的且耐受性良好 [NCT# 01918202]。 (C) 2017 Elsevier Ltd. 保留所有权利。
Phosphodiesterase 10A (PDE10A) is an enzyme highly enriched in the striatal medium spiny neurons. It is involved in the regulation of cytoplasmic levels of cAMP and cGMP and signaling within the basal ganglia. This study with PDE10A radioligand [F-18]MNI-659 was designed to measure the enzyme occupancy of PF-02545920 in 8 healthy male volunteers (48 +/- 4 years) after a single oral dose (10 mg or 20 mg) and to evaluate safety and tolerability. Arterial blood sampling was performed to obtain a metabolite-corrected plasma input function for the quantification of [18F]MNI-659 binding to PDE10A. The occupancy of PF-02545920 was calculated with two different methods: In Method 1, [18F]MNI-659 enzyme occupancy was calculated from the estimates of binding potential, using the cerebellum as a reference region; in Method 2, occupancy was estimated from the slope of the revised Lassen's plot. Serum concentrations of PF-02545920 were measured to determine the relationship between concentration and occupancy. Based on Method 1, striatal PDE10A occupancy increased with increasing PF-02545920 dose: 14-27% at 10 mg dose (N = 4) and 45-63% at 20 mg dose (N = 3). Comparable occupancies were observed using Lassen's plot Method 2: 10 mg: 14-37%; 20 mg: 46-55%. The relationship between exposure and occupancy was best described using an Emax model. The serum concentration associated with 50% occupancy was estimated to be 93.2 ng/mL. Single oral doses of 10 mg or 20 mg of PF-02545920 were safe and well tolerated in healthy male volunteers [NCT# 01918202]. (C) 2017 Elsevier Ltd. All rights reserved.