PET/CT study of dopamine transporter (DAT) binding with the triple reuptake inhibitor toludesvenlafaxine in rats and humans

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. [¹⁸F]FECNT and [¹¹C]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_{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.

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).