Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

Functional Characterization of 5-HT1B Receptor Drugs in Nonhuman Primates Using Simultaneous PET-MR

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Cortical and Subcortical Effects of Transcutaneous Spinal Cord Stimulation in Humans with Tetraplegia

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Effects of sensorineural hearing loss on cortical synchronization to competing speech during selective attention

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Differences in frontal network anatomy across primate species

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Hot and cold cognitive disturbances in antidepressant-free patients with major depressive disorder: a NeuroPharm study

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Structural brain abnormalities associated with cognitive impairments in bipolar disorder

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. NeuroPharm study: EEG wakefulness regulation as a biomarker in MDD

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Parkinson patients have a presynaptic serotonergic deficit: A dynamic deep brain stimulation PET study

    Research output: Contribution to journalJournal articleResearchpeer-review

View graph of relations

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT1B receptor (5-HT1BR) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates (n = 3), we used positron emission tomography (PET) imaging with the radioligand [(11)C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT1BR occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT1BR partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT1BR occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT1BR densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HT1BR agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT1BR cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT1BR and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin.SIGNIFICANCE STATEMENT We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT1B receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial and temporal effects on brain hemodynamics provide information about pharmacologically driven downstream CNS drug effects; the brain hemodynamic response shows characteristic dose-related effects that differ depending on agonistic or antagonistic drug characteristics and on local 5-HT1B receptor density. The technique lends itself to a comprehensive in vivo investigation and understanding of drugs' effects in the brain.

Original languageEnglish
JournalThe Journal of Neuroscience : the official journal of the Society for Neuroscience
Volume37
Issue number44
Pages (from-to)10671-10678
Number of pages8
ISSN0270-6474
DOIs
Publication statusPublished - 1 Nov 2017

    Research areas

  • Animals, Brain, Dose-Response Relationship, Drug, Drug Partial Agonism, Macaca mulatta, Magnetic Resonance Imaging, Male, Positron-Emission Tomography, Receptor, Serotonin, 5-HT1B, Serotonin 5-HT1 Receptor Agonists, Serotonin 5-HT1 Receptor Antagonists, Journal Article

ID: 52018846