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

Objectives In vivo PET studies of the 5-HT1A receptor have been limited to antagonist radiotracers, and they do not distinguish high and low affinity conformations of G-protein coupled receptors and are less likely to be sensitive to displacement by intra-synaptic serotonin levels. We have recently developed a novel 5-HT1A agonist PET radiotracer [11C]CUMI-101. This study evaluates the sensitivity of [11C]CUMI-101 binding to an increase in intra-synaptic serotonin induced by intravenous (i.v.) citalopram and fenfluramine.

Methods PET scans were performed in two adult male Papio Anubis with an ECAT EXACT HR+ scanner after an i.v. bolus injection of 4.5 ± 1.5 mCi of [11C]CUMI-101. Binding potential (BPF=Bmax/KD) was measured before (n=10 scans) and 20 min after an elevation of intra-synaptic serotonin by i.v. citalopram (2 mg/kg i.v., n=3; 4 mg/kg i.v., n=3) and fenfluramine (2.5 mg/kg i.v., n=3) using a free fraction and metabolite-corrected arterial input function. Occupancy results were also estimated by the Lassen graphical approach that requires no reference region.

Results Both the citalopram and the fenfluramine dose response were significant for BPF (p=0.031 and p=0.049 respectively). The Lassen graphical approach estimated 14.98%, 30.39% and 23.74% average occupancy in response to citalopram 2 mg/kg, 4 mg/kg and fenfluramine 2 mg/kg respectively.

Conclusions [11C]CUMI-101 5-HT1A binding is sensitive to large increase in intra-synaptic serotonin levels in response to robust pharmacological challenges. Although these modest changes in BPF make it unlikely that this ligand will detect small changes in intra-synaptic 5-HT under physiological conditions, future work will undoubtedly focus on evaluating its utility in measuring the responsiveness of the 5-HT system to pharmacological challenges in health and disease.

Research Support This work was supported in part by PHS grants MH076258, MH062185, MH077161 and MH040695