Journal Article

Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

Kai-Chun Yang, Vladimir Stepanov, Stefan Martinsson, Anders Ettrup, Akihiro Takano, Gitte M Knudsen, Christer Halldin, Lars Farde and Sjoerd J Finnema

in International Journal of Neuropsychopharmacology

Published on behalf of International College of Neuropsychopharmacology

Volume 20, issue 9, pages 683-691
ISSN: 1461-1457
Published online June 2017 | e-ISSN: 1469-5111 | DOI: https://dx.doi.org/10.1093/ijnp/pyx051
Fenfluramine Reduces [11C]Cimbi-36 Binding to the 5-HT2A Receptor in the Nonhuman Primate Brain

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  • Clinical Pharmacology and Therapeutics
  • Neurology
  • Psychiatry
  • Neuroscience

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Abstract

Background

[11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain.

Methods

Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region.

Results

Fenfluramine significantly decreased [11C]Cimbi-36 (26–62%) and [11C]AZ10419369 (35–58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex.

Conclusions

The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain.

Keywords: [11C]Cimbi-36; [11C]AZ10419369; [11C]MDL 100907; fenfluramine; serotonin

Journal Article.  5922 words.  Illustrated.

Subjects: Clinical Pharmacology and Therapeutics ; Neurology ; Psychiatry ; Neuroscience

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