Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
Eur J Nucl Med Mol Imaging. 2024 Jul;51(9):2638-2648. doi: 10.1007/s00259-024-06700-2. Epub 2024 Apr 8.
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.
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. [F]FECNT and [C]CFT were used as PET/CT radioactive tracer for rat and human studies, respectively.
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 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.
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.
NCT05905120. Registered 14 June 2023. (retrospectively registered).
托鲁地文拉法辛是一种新开发的抗抑郁药，属于三重再摄取抑制剂类。尽管有体外证据表明托鲁地文拉法辛可抑制 5-羟色胺（5-HT）、去甲肾上腺素（NE）和多巴胺（DA）的再摄取，但尚无体内证据表明托鲁地文拉法辛与 DAT 结合并增加 DA 水平，而这种机制被认为有助于其良好的临床疗效。
正电子发射断层扫描/计算机断层扫描（PET/CT）用于检查健康大鼠和人体的 DAT 结合能力，微透析用于检查大鼠纹状体的 DA 水平。[F]FECNT 和 [C]CFT 分别用作大鼠和人体研究的 PET/CT 放射性示踪剂。
在大鼠中，静脉注射 9 mg/kg 的盐酸托鲁地文拉法辛后，通过微量泵输注 3 mg/kg，在 45 分钟扫描期间，纹状体 DAT 的结合率为 3.7-32.41%，下丘脑 DAT 的结合率为 5.91-17.52%。口服 32 mg/kg 的盐酸托鲁地文拉法辛可显著增加纹状体 DA 水平，AUC 增加 63.9%。在健康志愿者中，每日口服 160 mg 盐酸托鲁地文拉法辛缓释片 4 天，分别在 6 小时和 10 小时给药后，基底神经节 DAT 的平均占有率为 8.04%±7.75%和 8.09%±7.00%。
这些结果首次使用 PET/CT 证实了托鲁地文拉法辛在大鼠和人体中的 DAT 结合，并证实其升高脑 DA 水平，这可能有助于理解托鲁地文拉法辛等三重再摄取抑制剂的独特药理学和功能效应。
NCT05905120. 2023 年 6 月 14 日注册（回溯性注册）。
Zotero 插件