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

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Abstract

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 AUC0 − 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).

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Data availability

The data are available upon request at the corresponding author’s address.

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Funding

This study was supported by Collaborative Innovation Center Project of Translational Medicine, Shanghai Jiaotong University School of Medicine, TM202116PT (2021–2023) and STI2030-Major Projects (2022ZD0213800).

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Author notes

  1. Zhiwei Huang and Junhao Wu have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Zhiwei Huang, Yumei Wei & Yifeng Shen

  2. Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China

    Junhao Wu, Yihui Guan & Fang Xie

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  1. Zhiwei Huang
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Contributions

Fang Xie and Yifeng Shen contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zhiwei Huang, Junhao Wu, Yihui Guan and Yumei Wei. The first draft of the manuscript was written by Zhiwei Huang and Junhao Wu. All authors reviewed and approved the final manuscript.

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Correspondence to Fang Xie or Yifeng Shen.

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The Shanghai Mental Health Center ethics committee approved the study protocol and informed consent form (2022-90). All subjects signed written informed consent. The study adhered to the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice (ICH GCP) guidelines.

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Huang, Z., Wu, J., Guan, Y. et al. PET/CT study of dopamine transporter (DAT) binding with the triple reuptake inhibitor toludesvenlafaxine in rats and humans. Eur J Nucl Med Mol Imaging (2024). https://doi.org/10.1007/s00259-024-06700-2

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