Effect of fenfluramine-induced increases in serotonin release on [F-18]MPPF]binding: A continuous infusion PET study in conscious monkeys

[F-18]MPPF is a selective and reversible antagonist to the serotonin-1A (5-HT1A) receptor. The aim of the present study was to investigate whether the binding of [18F]MPPF is sensitive to increases in 5-HT levels. We used the 5-HT releasing agent and reuptake inhibitor fenfluramine (FEN) to increase the concentration of 5-HT. [F-18]MPPF binding was assessed using positron emission tomography (PET) in conscious monkeys. Possible effects of blood flow on ligand binding were excluded by using a bolus-infusion paradigm. Control scans were obtained to assess the state of ligand equilibrium. FEN (5 or 10 mg/kg, i.v.) was administered between 90 and 130 min after the start of the [F-18]MPPF infusion. The binding potential (BP) was calculated for an early interval (30 min preceding FEN administration) and late interval (20-50 min after administration of FEN). Microdialyses results showed a 20- and 35-fold increase in extracellular 5-HT levels in the prefrontal cortex after injection of FEN at a dose of 5 mg/kg and 10 mg/kg respectively. However, despite these large increases in 5-HT levels, no differences in BP were found between the control and FEN scans. These results may imply that the majority of 5-HT1A receptors is in the low affinity state in the living brain.