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Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: Dopamine transporter occupancy as measured by PET
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
2014 (English)In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 24, no 2, 251-261 p.Article in journal (Refereed) Published
Abstract [en]

Tesofensine (TE) is a novel triple monoannine 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 [C-11]beta 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 signnoid 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.

Place, publisher, year, edition, pages
2014. Vol. 24, no 2, 251-261 p.
Keyword [en]
Positron emission tomography, Dopamine re-uptake, DAT, Chronic treatment, Neurochemistry, Drug development
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-221981DOI: 10.1016/j.euroneuro.2013.10.007ISI: 000331680100009OAI: oai:DiVA.org:uu-221981DiVA: diva2:710873
Available from: 2014-04-08 Created: 2014-04-07 Last updated: 2014-04-08Bibliographically approved

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Appel, LieuweLångström, Bengt
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Section of Nuclear Medicine and PETDepartment of PharmacyPhysical Organic Chemistry
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