Confirmation of fenfluramine effect on 5-HT 1B receptor binding of 11CAZ10419369 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 11CAZ10419369. 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 11CAZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable Kbol values. The fenfluramine effect on 11CAZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on 11CAZ10419369 binding potential (BPND) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BPND of the occipital cortex decreased by 39%, from 1.38±0.04 to 0.84±0.09. This study confirms that the new 5-HT1B receptor radioligand 11CAZ10419369 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 11CAZ10419369 and PET. © 2012 ISCBFM All rights reserved.