Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET.
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]βCIT-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.
PET Centre, Department of Medical Imaging, Uppsala University Hospital, S-751 85 Uppsala, Sweden; Section of Nuclear Medicine and PET, Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden. Electronic address: lieuwe.appel@akademiska.se.
Lieuwe
L
Appel
Department of Pharmaceutical Sciences, Uppsala University, Uppsala, Sweden.
Mats
M
Bergström
NeuroSearch A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.
Jørgen
J
Buus Lassen
Department of Biochemistry and Organic Chemistry, Uppsala University, Uppsala, Sweden; Department of Nuclear Medicine, PET & Cyclotron Unit, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
Bengt
B
Långström
D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors*; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008954:Models, Biological; D009662:Nortropanes; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D055815:Young Adult
D019440:Anti-Obesity Agents; D015306:Biogenic Monoamines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D050483:Dopamine Plasma Membrane Transport Proteins; C097058:N-(2-fluoroethyl)-2-carbomethoxy-3-(4-iodophenyl)nortropane; D009662:Nortropanes; D019275:Radiopharmaceuticals; C518479:Tesofensine
Chronic treatment; DAT; Dopamine re-uptake; Drug development; Neurochemistry; Positron emission tomography