Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study

Abstract

Identification of a biomarker that can inform on extracellular serotonin (5-HT) levels in the brains of living humans would enable greater understanding of the way brain circuits are modulated by serotonergic neurotransmission. Substantial evidence from studies in animals and humans indicates an inverse relationship between central 5-HT tonus and 5-HT type 4 receptor (5-HT4R) density, suggesting that 5-HT4R receptor density may be a biomarker marker for 5-HT tonus. Here, we investigated whether a 3-week administration of a selective serotonin reuptake inhibitor, expected to increase brain 5-HT levels, is associated with a decline in brain 5-HT4R binding. A total of 35 healthy men were studied in a placebo-controlled, randomized, double-blind study. Participants were assigned to receive 3 weeks of oral dosing with placebo or fluoxetine, 40 mg per day. Brain 5-HT4R binding was quantified at baseline and at follow-up with [(11)C]SB207145 positron emission tomography (PET). Three weeks of intervention with fluoxetine was associated with a 5.2% reduction in brain 5-HT4R binding (P=0.017), whereas placebo intervention did not change 5-HT4R binding (P=0.52). Our findings are consistent with a model, wherein the 5-HT4R density adjusts to changes in the extracellular 5-HT tonus. Our data demonstrate for the first time in humans that the imaging of central 5-HT4R binding may be used as an in vivo biomarker of the central 5-HT tonus.

The Center for Integrated Molecular Brain Imaging (Cimbi) database

“…2) and established normative data for the 5-HTT , the 5-HT 2A (Adams et al, 2004) and the 5-HT 4 (Madsen et al, 2011b) receptors. A novel agonist radioligand for 5-HT 2A receptor PET studies, [11C]Cimbi-36, has also been developed and validated in humans (Ettrup et al, 2014) and 5-HT 4 receptor binding has been shown to be inversely related to 5-HT brain levels (Fisher et al, 2012;Haahr et al, 2014).…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…Other recent initiatives include work with the 5-HT 4 receptor antagonist [ 11 C]SB207145 19 and the 5-HT 2A receptor agonist [ 11 C]Cimbi-36. Initial evaluation of [ 11 C]Cimbi-36 demonstrated serotonin sensitivity with changes that are detectable with PET when the serotonin release is sufficiently high 20 .…”

Fluctuations in [11C]SB207145 PET Binding Associated with Change in Threat-Related Amygdala Reactivity in Humans

“…All participants were generally healthy (see Supplementary Materials and Methods for more details) as described previously (Haahr et al, 2014). Of the 35 participants who were recruited for the study, four did not complete the entire protocol (two because of PET scanner failure, one elected to dropout, and one did not complete the fMRI paradigm).…”

“…Thus, our sample consisted of 31 individuals. fMRI data included here have not been previously described, whereas PET data included here have been reported previously (Fisher et al, 2012;Haahr et al, 2014;Haahr et al, 2013).…”

“…Three-week fluoxetine intervention (40 mg) was associated with a 5% decrease in 5-HT 4 binding (Haahr et al, 2014). This same cohort completed a gender-matching threat-related face fMRI paradigm, offering a unique opportunity to determine the association between fluctuations in central serotonin levels, assessed with PET, and threat-related corticolimbic reactivity assessed with fMRI.…”