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

Abstract

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-HT(1A) agonist radiotracer [(11)C]CUMI-101. This study evaluates the sensitivity of [(11)C]CUMI-101 binding to increases in intrasynaptic serotonin induced by intravenous citalopram and fenfluramine. Two Papio anubis were scanned, using [(11)C]CUMI-101 intravenous bolus of 4.5 ± 1.5 mCi. Binding potential (BP(F)=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 BP(F) (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. [(11)C]CUMI-101 binding is sensitive to a large increase in intrasynaptic serotonin in response to robust pharmacological challenges. These modest changes in BP(F) 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.

Figure 1

Graphical analysis applied to PET occupancy studies. Data are collected from a single [¹¹C]CUMI-101 study in baboons at baseline and after intravenous administration of a 5-HT_1A antagonist WAY100635 at 0.5 mg/kg (diamonds); black circles and triangles represent data at baseline and after intravenous administration of citalopram at 4 mg/kg and 2 mg/kg, respectively (single studies). In all cases, the estimated V_ND values (or x axis intercept of the linear fit), were not included in the regression analysis. PET, positron emission tomography; 5-HT_1A, 5-hydroxytryptamine_1A.

Figure 2

Graphical analysis applied to PET occupancy studies. Data are collected from [¹¹C]CUMI-101 study in baboons at baseline and after intravenous administration of citalopram 4 mg/kg (circles); citalopram 2 mg/kg (diamonds), and fenfluramine 2 mg/kg (triangles), respectively (each data points representing means from three experiments). In all cases, the estimated V_ND values were constrained to estimates from the blocks achieved using cold 0.5 mg/kg WAY100635 (see Figure 1). PET, positron emission tomography.

Figure 3

Mean V_T (top) and BP_F (bottom) of [¹¹C]CUMI-101 after citalopram (2 or 4 mg/kg) and fenfluramine (2.5 mg/kg) intravenously. These values were derived from the LEGA model with scan duration of 100 minutes. Error bars represent the s.d. LEGA, likelihood estimation in graphical analysis.