Fenfluramine‐induced serotonin release decreases [¹¹C]AZ10419369 binding to 5‐HT_1B‐receptors in the primate brain

Abstract

The need for positron emission tomography (PET)-radioligands that are sensitive to changes in endogenous serotonin (5-HT) levels in brain is recognized in experimental and clinical psychiatric research. We recently developed the novel PET radioligand [(11)C]AZ10419369 that is highly selective for the 5-HT(1B) receptor. In this PET-study in three cynomolgus monkeys, we examined the sensitivity of [(11)C]AZ10419369 to altered endogenous 5-HT levels. Fenfluramine-induced 5-HT release decreased radioligand binding in a dose-dependent fashion with a regional average of 27% after 1 mg/kg and 50% after 5 mg/kg. This preliminary study supports that [(11)C]AZ10419369 is sensitive to endogenous 5-HT levels in vivo and may serve as a tool to examine the pathophysiology and treatment of major psychiatric disorders.

Confirmation of Fenfluramine Effect on 5-HT1B Receptor Binding of [11C]AZ10419369 using an Equilibrium Approach

“…The here reported mean fenfluramine effect on [ 11 C]AZ10419369 binding across eight brain regions (À12% at 1.0 mg/kg; À33% and À34% at 5.0 mg/kg) is in line with our previous study, in which [ 11 C]AZ10419369 was administered as a bolus injection (À27% at 1.0 mg/kg; À50% at 5.0 mg/kg; Finnema et al, 2010). A comparable effect of fenfluramine on radioligand binding has more recently also been showed using the 5-HT 1A receptor radioligand [ 11 C]CUMI-101 (Milak et al, 2010) and the 5-HT 1B receptor radioligand […”

Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369

“…It may therefore be assumed that elevation in 5-HT levels in response to AZD3783 administration may reduce radioligand binding to brain 5-HT 1B receptors. Sensitivity of [ 11 C]AZ10419369 to changes in endogenous 5-HT has indeed been previously demonstrated by fenfluramine challenge in monkeys (Finnema et al 2010). Therefore, it cannot be excluded that occupancy values measured in the present study result from a combination of AZD3783 Fig.…”

Serotonin transporter occupancy by escitalopram and citalopram in the non-human primate brain: a [11C]MADAM PET study

“…We previously demonstrated that the potent serotonin releaser fenfluramine reduced the binding of the 5-HT 1B receptor radioligand [ 11 C]AZ10419369 in non-human primates by up to 50 % (Finnema et al 2010(Finnema et al , 2012, and similar results have been reported by others using the 5-HT 1B receptor radioligand [ 11 C]P943 (Cosgrove et al 2011;Ridler et al 2011) or the 5-HT 1A receptor radioligand [ 11 C]CUMI-101 (Milak et al 2011). The effects of single SSRI doses have also been evaluated in anaesthetized non-human primates (NHPs) in preparation for studies in human.…”