NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo

  title={NET occupancy by clomipramine and its active metabolite, desmethylclomipramine, in non-human primates in vivo},
  author={Akihiro Takano and Sangram Nag and Bal{\'a}zs Guly{\'a}s and Christer Halldin and Lars Farde},
RationaleNorepinephrine transporter (NET) is one of the key targets for antidepressants such as combined serotonin and norepinephrine reuptake inhibitors as well as some of the tricyclic antidepressants. Clomipramine, a tricyclic antidepressant, has been reported to have an active metabolite, desmethylclomipramine, which has high affinity for NET in vitro. However, the NET occupancy of clomipramine and desmethylclomipramine has not fully been evaluated in vivo.ObjectivesIn this positron… 

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR.

This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiAPine XR) at doses relevant in the treatment of depression, and demonstrated the first demonstration of NET occupancy by an antipsychotic in the human brain.

Therapeutic doses of buspirone block D3 receptors in the living primate brain.

For oral buspirone to achieve greater than 80% sustained D3R occupancy, as might be needed to treat addiction, higher doses than those used to treat anxiety (maximal 60 mg) will be required.

Serum clomipramine and desmethylclomipramine levels in a CYP2C19 and CYP2D6 intermediate metabolizer.

The case of a 29-year-old male with diagnoses of depression and obsessive compulsive disorder who had trialed and failed a dozen psychiatric medications, and had most recently been taking clomipramine for approximately 2.5 years, is presented.

Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹⁸F]FMeNER-D₂.

Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is

Serotonin transporter occupancy with TCAs and SSRIs: a PET study in patients with major depressive disorder

It is supported that TCAs and SSRIs have a shared mechanism of action by inhibition of 5-HTT, and 5- HTT affinity correlated with the recommended clinical dose.

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the

Neuroimaging in Psychiatric Drug Development and Radioligand Development for New Targets

To widen the use of PET, the development of the PET radioligands for new targets is vital, and several criteria and characteristics such as binding affinity, selectivity and lipophilicity are important when selecting new PET Radioligand candidates for targets in brain.

Impact of medications on mIBG uptake, with specific attention to the heart: Comprehensive review of the literature

As there is strong evidence for inhibition of mIBG uptake in only a small number of compounds, clinical decisions regarding withdrawal of concomitant medications should be individualized by considering the potential consequences of a false-positive cardiac imaging result.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

  • C. EapG. Gründer C. Hiemke
  • Medicine, Biology
    The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry
  • 2021
There are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/ or phenotyping should be applied as valid tools of precision medicine.



N-Desalkylquetiapine, a Potent Norepinephrine Reuptake Inhibitor and Partial 5-HT1A Agonist, as a Putative Mediator of Quetiapine's Antidepressant Activity

The data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-DesalkylquetiAPine through NET inhibition and partial 5-HT1A agonism.

Regional distribution of clomipramine and desmethylclomipramine in rat brain and peripheral organs on chronic clomipramine administration

The cerebral cortex had the highest concentration of clomipramine, with successively lower concentrations in the hypothalamus, striatum, cerebellum, hippocampus and brainstem, while in the heart, only the metabolite was detected.

Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[18F]FMeNER-D2

The results indicate that clinical doses of atomoxetine would occupy NET almost completely, regionally and uniformly as the plasma concentration of atomxetine increased.

Pharmacological profile of antidepressants and related compounds at human monoamine transporters.

High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography.

Clinical doses of clomipramine and fluvoxamine occupied approximately 80% of 5- HTT, and dose escalation would have minimal effect on 5-HTT blockade, and occupational occupancy increased in a curvilinear manner.

Norepinephrine transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2

The occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[18F]FMeNER-D2 with results observed from 16% to 41%.

Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNER-D2

This is the first in vivo PET study to successfully demonstrate the ability to measure a dose-dependent change in NET occupancy in brain using (S,S)-[18F]FMeNER-D2 in humans.

Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study.

Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses, which suggests that 80% 5-HTT blockade is important for therapeutic effect.