Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: Dopamine transporter occupancy as measured by PET

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• 作者：Lieuwe Appel ; Mats Bergstr枚m ; J酶rgen Buus Lassen ; Bengt L氓ngstr枚m
• 关键词：Positron emission tomography ; Dopamine re-uptake ; DAT ; Chronic treatment ; Neurochemistry ; Drug development
• 刊名：European Neuropsychopharmacology
• 出版年：February, 2014
• 年：2014
• 卷：24
• 期：2
• 页码：251-261
• 全文大小：769 K

文摘

Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [¹¹C]尾CIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E_max model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT.