Confirmation of Fenfluramine Effect on 5-HT_1B Receptor Binding of [¹¹C]AZ10419369 using an Equilibrium Approach

Abstract

Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [11 C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [11 C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable K bol values. The fenfluramine effect on [ 11 C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [11 C]AZ10419369 binding potential (BP ND ) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BP ND of the occipital cortex decreased by 39%, from 1.38 ± 0.04 to 0.84 ± 0.09. This study confirms that the new 5-HT 1B receptor radioligand [11 C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [11 C]AZ10419369 and PET.

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.…”

Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain

“…The 5-HT 1B receptor functions partly as an autoreceptor (Sari, 2004) and is therefore expected to be sensitive to alterations in endogenous serotonin concentration. Indeed, in non-human primates, [ 11 C]AZ10419369 has proven useful to study regional changes in endogenous serotonin concentration after administration of the serotonin-releasing compound, fenfluramine (Finnema et al, 2010(Finnema et al, , 2012.…”

No correlation between serotonin and its metabolite 5-HIAA in the cerebrospinal fluid and [11C]AZ10419369 binding measured with PET in healthy volunteers

“…The application of PET to measure changes in serotonin levels has been hampered by a lack of suitable radioligands (Paterson et al, 2010). There are promising results with the recently developed 5-HT 1B receptor antagonist [ 11 C]AZ10419369, with decreased binding in response to pharmacologically induced serotonin release (Finnema et al, 2012) and high doses of a selective serotonin reuptake inhibitor (SSRI) in nonhuman primates (Nord et al, 2013). However, the effect of baseline serotonin levels on [ 11 C]AZ10419369 binding in humans has not yet been studied.…”