In vivo serotonin-sensitive binding of [C-11]CUMI-101: a serotonin 1A receptor agonist positron emission tomography radiotracer

Positron emission tomography studies of 5-hydroxytryptamine (5-HT)(1A) receptors have hitherto been limited to antagonist radiotracers. Antagonists do not distinguish high/low-affinity conformations of G protein-coupled receptors and are less likely to be sensitive to intrasynaptic serotonin levels. We developed a novel 5-HT1A agonist radiotracer [C-11]CUMI-101. This study evaluates the sensitivity of [C-11] CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [C-11] CUMI-101 intravenous bolus of 4.5 +/- 1.5 mCi. Binding potential (BPF = B-avail/K-D) was measured before (n = 10) and 20 minutes after elevation of intrasynaptic serotonin by intravenous citalopram (2 mg/kg, n = 3; 4 mg/kg, n = 3) and fenfluramine (2.5 mg/kg, n = 3) using a metabolite-corrected arterial input function. Occupancy was also estimated by the Lassen graphical approach. Both citalopram and fenfluramine effects were significant for BPF (P = 0.031, P = 0.049, respectively). The Lassen approach estimated 15.0, 30.4, and 23.7% average occupancy after citalopram 2 mg/kg, 4 mg/kg, and fenfluramine 2.5 mg/kg, respectively. [C-11] CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BPF may make it unlikely that this ligand will detect changes in intrasynaptic 5-HT under physiologic conditions; future work will focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 243-249; doi:10.1038/jcbfm.2010.83; published online 23 June 2010