PURPOSE Histamine H3 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 H3 receptors. METHODS To measure the histamine H3 receptor occupancy by enerisant, positron emission tomography studies using [11C]TASP457, a specific radioligand for histamine H3 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 H3 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.

中文翻译：

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enerisant 对组胺 H3 受体占有率的药代动力学和药效学评估：使用新型 H3 结合配体 [11C]TASP457 进行的人体 PET 研究。

目的 组胺 H3 受体拮抗剂和反向激动剂已被广泛用于治疗睡眠-觉醒、神经认知和相关疾病。然而，潜在的副作用，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。本研究的目的是估计 enerisant 的药代动力学和药效学，它是一种新型的组胺 H3 受体拮抗剂和反向激动剂。方法 为了通过 enerisant 测量组胺 H3 受体的占有率，使用 [11C]TASP457（一种组胺 H3 受体的特异性放射性配体）对 12 名健康男性在基线和口服盐酸 enerisant 后 2 小时进行了正电子发射断层扫描研究。对于其中三个科目，在给药后 6 小时和 26 小时进行了两次额外的扫描。然后分析了 enerisant 的受体占有率与其剂量和血浆浓度之间的关系。结果 恩瑞生盐酸盐的给药以剂量依赖性方式降低了放射性配体的结合。估计的 2 小时受体占有率值随其剂量或血浆浓度而变化。在较高剂量（25 和 12.5 毫克）的两名受试者中，占用的时间过程显示出持续的高水平（> 85%）。最初的 2 小时和 6 小时占用率也很高，较低的剂量为 5 毫克，但在 26 小时下降到 69.7%。结论 enerisant 的目标参与在活的人类受试者的大脑中得到了证明。通过将 enerisant 的血浆浓度应用于 Hill 曲线，可以预测 enerisant 在 2 小时时对组胺 H3 受体的占有率。初步的时间进程调查显示，尽管药物的血浆浓度降低，但高剂量的 enerisant 的脑占用率持续较高。5 毫克或更少的剂量将适用于治疗发作性睡病，最初占用率很高，可以有效治疗发作性睡病，然后预期占用率会降低到避免这种药物在夜间失眠的不良副作用的水平，尽管有必要进行进一步的研究来证实这一说法，因为预期的减少是基于对一个主题的发现。试验注册 本研究在临床试验中进行了回顾性注册。