Pharmacokinetic and pharmacodynamic assessment of histamine H3 receptor occupancy by enerisant: a human PET study with a novel H3 binding ligand, [11C]TASP457
Pharmacokinetic and pharmacodynamic assessment of histamine H3 receptor occupancy by enerisant: a human PET study with a novel H3 binding ligand, [11C]TASP457
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DOI：
10.1007/s00259-021-05571-1
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发表时间：
2021-10-15
影响因子：
9.1
通讯作者：
Suhara, Tetsuya
中科院分区：
文献类型：
--
作者：
Kimura, Yasuyuki;Takahata, Keisuke;Suhara, Tetsuya
目的组胺H-3受体拮抗剂和反向激动剂已被广泛开发用于治疗睡眠-觉醒、神经认知和相关疾病。然而，潜在的不良反应，包括失眠，阻碍了这些药物的临床使用，可能是由于它们与靶分子的持续相互作用。本研究的目的是评价一种新型组胺H-3受体拮抗剂和反向激动剂enerisant的药代动力学和药效学。方法采用放射性配体[C-11] TASP 457对12名健康男性进行正电子发射断层扫描（PET）研究，分别于服药前和服药后2 h测定组胺H-3受体结合率。对于其中3例受试者，在给药后6 h和26 h进行了两次额外扫描。分析了受体结合率与剂量及血药浓度的关系。结果给予盐酸enerisant可降低放射性配体结合，并呈剂量依赖性。2 h时的估计受体结合率值随其剂量或血浆浓度的变化而变化。占用的时间过程显示，在较高剂量（25和12.5 mg）的两名受试者中持续存在高水平（> 85%）。在较低剂量5 mg时，最初2 h和6 h的占有率也较高，但在26 h时降至69.7%。结论在活体人脑中证实了enerisant的靶向作用。将兴奋药的血浆浓度应用于Hill’s图，可以预测兴奋药在2 h时对组胺H-3受体的占有率。初步的时间过程研究显示，尽管药物的血浆浓度不断下降，但高剂量的enerisant仍会导致持续的高脑占用率。5毫克或更少的剂量适用于治疗发作性睡病，最初的高占用率允许有效治疗发作性睡病，然后占用率水平预计将降低至避免该药物不必要的夜间失眠副作用的水平，尽管需要进一步研究来证实该声明，因为预期的降低是基于一名受试者的发现。试验注册本研究于2020年11月17日在ClinicalTrials.gov（NCT 04631276）上进行了回顾性注册。
Purpose Histamine H-3 receptor antagonists and inverse agonists have been extensively developed to treat sleep-wake, neurocognitive, and allied disorders. However, potential adverse effects, including insomnia, hampered the clinical use of these drugs, possibly due to their persistent interaction with the target molecules. The purpose of the present study was to estimate the pharmacokinetics and pharmacodynamics of enerisant, a novel antagonist and inverse agonist for histamine H-3 receptors. Methods To measure the histamine H-3 receptor occupancy by enerisant, positron emission tomography studies using [C-11]TASP457, a specific radioligand for histamine H-3 receptors, were performed in 12 healthy men at baseline and at 2 h after oral administration of enerisant hydrochloride. For three of these subjects, two additional scans were performed at 6 and 26 h after the administration. Relationships between the receptor occupancy by enerisant and its dose and plasma concentrations were then analyzed. Results Administration of enerisant hydrochloride decreased the radioligand binding in a dose-dependent manner. The estimated receptor occupancy values at 2 h varied as a function of its dose or plasma concentration. The time course of the occupancy showed persistently high levels (> 85%) in the two subjects with higher doses (25 and 12.5 mg). The occupancy was also initially high at 2 h and 6 h with the lower dose of 5 mg, but it decreased to 69.7% at 26 h. Conclusion The target engagement of enerisant was demonstrated in the brains of living human subjects. The occupancy of histamine H-3 receptors by enerisant at 2 h can be predicted by applying the plasma concentration of enerisant to Hill's plot. The preliminary time-course investigation showed persistently high brain occupancy with high doses of enerisant despite the decreasing plasma concentration of the drug. Five milligrams or less dose would be appropriate for the treatment for narcolepsy with initially high occupancy allowing for effective treatment of narcolepsy, and then the occupancy level would be expected to decrease to a level to avoid this drug's unwanted side effect of insomnia at night, although further research is warranted to confirm the statement since the expected decrease is based on the finding in one subject. Trial registration This study was retrospectively registered with ClinicalTrials.gov (NCT04631276) on November 17, 2020.