Purpose

Toludesvenlafaxine is a recently developed antidepressant that belongs to the triple reuptake inhibitor class. Despite the in vitro evidence that toludesvenlafaxine inhibits the reuptake of serotonin (5-HT), norepinephrine (NE) and dopamine (DA), there is no in vivo evidence that toludesvenlafaxine binds to DAT and increases DA level, a mechanism thought to contribute to its favorable clinical performance.

Methods

Positron emission tomography/computed tomography (PET/CT) was used to examine the DAT binding capacity in healthy rats and human subjects and microdialysis was used to examine the striatal DA level in rats. [¹⁸F]FECNT and [¹¹C]CFT were used as PET/CT radioactive tracer for rat and human studies, respectively.

Results

In rats, 9 mg/kg of toludesvenlafaxine hydrochloride (i.v.) followed by an infusion of 3 mg/kg via minipump led to the binding rate to striatum DAT at 3.7 – 32.41% and to hypothalamus DAT at 5.91 – 17.52% during the 45 min scanning period. 32 mg/kg oral administration with toludesvenlafaxine hydrochloride significantly increased the striatal DA level with the AUC_{0 − 180 min} increased by 63.9%. In healthy volunteers, 160 mg daily toludesvenlafaxine hydrochloride sustained-release tablets for 4 days led to an average occupancy rates of DAT at 8.04% ± 7.75% and 8.09% ± 7.00%, respectively, in basal ganglion 6 h and 10 h postdose.

Conclusion

These results represent the first to confirm the binding of toludesvenlafaxine to DAT in both rats and humans using PET/CT, and its elevation of brain DA level, which may help understand the unique pharmacological and functional effects of triple reuptake inhibitors such as toludesvenlafaxine.

ClinicalTrials.gov identifiers

: NCT05905120. Registered 14 June 2023. (retrospectively registered).

中文翻译：

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大鼠和人体内多巴胺转运蛋白 (DAT) 与三重再摄取抑制剂甲苯地文拉法辛结合的 PET/CT 研究

目的

Toludesvenlafaxine 是一种最近开发的抗抑郁药，属于三重再摄取抑制剂类。尽管体外证据表明甲苯地文拉法辛抑制血清素（5-HT）、去甲肾上腺素（NE）和多巴胺（DA）的再摄取，但没有体内证据表明甲苯地文拉法辛与 DAT 结合并增加 DA 水平，这种机制被认为有助于其良好的临床表现。

方法

使用正电子发射断层扫描/计算机断层扫描（PET/CT）检查健康大鼠和人类受试者的DAT结合能力，并使用微透析检查大鼠纹状体DA水平。 [ ¹⁸ F]FECNT和[ ¹¹ C]CFT分别用作大鼠和人类研究的PET/CT放射性示踪剂。

结果

在大鼠中，9 mg/kg 盐酸甲苯地文拉法辛 (iv)，然后通过微型泵输注 3 mg/kg，在 45 分钟内与纹状体 DAT 的结合率为 3.7 – 32.41%，与下丘脑 DAT 的结合率为 5.91 – 17.52%扫描周期。口服32 mg/kg盐酸甲苯甲文拉法辛显着增加纹状体DA水平，AUC _{0 – 180 min}增加63.9%。在健康志愿者中，每天服用 160 mg 盐酸托鲁地文拉法辛缓释片，连续 4 天，给药后 6 小时和 10 小时，基底神经节中 DAT 的平均占有率分别为 8.04% ± 7.75% 和 8.09% ± 7.00%。

结论

这些结果首次使用 PET/CT 在大鼠和人类中证实了甲苯地文拉法辛与 DAT 的结合，以及其脑内 DA 水平的升高，这可能有助于了解三重再摄取抑制剂（如甲苯地文拉法辛）的独特药理和功能作用。

ClinicalTrials.gov 标识符

：NCT05905120。注册日期：2023 年 6 月 14 日。（追溯注册）。