In vivo biased agonism at 5-HT1A receptors: characterisation by simultaneous PET/MR imaging

Abstract

In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT radiotracer, [F]MPPF. Drug occupancy was evaluated after injection at 50 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT receptor occupancy was found to be dose-dependent for both agonists, but differed in magnitude and spatial distribution at equal doses with distinct BOLD patterns. Functional connectivity, as measured by BOLD signal temporal correlations between regions, was also differently modified by NLX-112 or NLX-101. Voxel-based correlation analyses between PET and fMRI suggested that NLX-112 stimulates both 5-HT autoreceptors and post-synaptic receptors, whereas NLX-101 preferentially stimulates post-synaptic cortical receptors. In cingulate cortex, the agonists induced opposite BOLD signal changes in response to receptor occupancy. These data constitute the first simultaneous exploration of 5-HT occupancy and its consequences in terms of brain activation, and demonstrates differential signalling by two 5-HT-biased agonists. Combined PET/fMRI represents a powerful tool in neuropharmacology, and opens new ways to address the concept of biased agonism by translational approaches.

Is There a Role for GPCR Agonist Radiotracers in PET Neuroimaging?

“…It also showed region-specific uptake changes in isoflurane-anesthetized animals, contrary to [ 18 F]MPPF for which global increase throughout the brain was observed (Yokoyama et al, 2016). Top design a radiotracer that would be easier to quantify, the structural analog [ 18 F]F13640 was recently evaluated (Vidal et al, 2018). F13640 also exhibits high selectivity for 5-HT 1A , but intermediate affinity (K i = 1 nM) compared to the previous two attempts.…”

“…Of the numerous attempts to develop a radiotracer sensitive to serotonin release, only a few experiments with [ 11 C]CUMI-101 (Milak et al, 2011) ([ 18 F]F13640 (Vidal et al, 2018) and [ 11 C]Cimbi36 (Jorgensen et al, 2017; Yang et al, 2017) showed sensitivity. These difficulties suggest notable differences between dopamine and serotonin competition systems: degree of receptor availability, proportion of high-affinity state receptors, and size of the accessible receptor pool (Paterson et al, 2010).…”

“…The authors attributed these differences to the biased agonism of F13714, interacting with specific G protein subtypes and targeting a specific brain region composed of presynaptic receptors: raphe striatum and thalamus. The notion of biased agonism was also recently explored by PET/MR imaging, and contributes to defining the existence of biased agonism on 5-HT 1A receptors (Vidal et al, 2018). In the kappa-opioid receptor, differences in the dynamics of receptor structure induced by the agonist [ 11 C]GR103545 versus the antagonists [ 11 C]LY2795050 and [ 11 C]LY2459989 were used to explain the in vivo discrepancies observed on PET imaging (Placzek et al, 2018).…”

Overcoming Resistance to Selective Serotonin Reuptake Inhibitors: Targeting Serotonin, Serotonin-1A Receptors and Adult Neuroplasticity

“…This could reflect inadequate dosing (Martinez et al, 2000), non-selective effects of pindolol on both 5-HT1A auto- and heteroreceptors (Newman-Tancredi et al, 2001), or antagonism of beta-adrenergic receptors. Partial block of postsynaptic 5-HT1A receptors by pindolol may prevent pindolol’s benefits due to block of 5-HT1A autoreceptors, emphasizing the need for compounds with higher selectivity to block presynaptic or activate post-synaptic 5-HT1A receptors (Garcia-Garcia et al, 2014; Vidal et al, 2018).…”

Biomarkers, designs, and interpretations of resting‐state fMRI in translational pharmacological research: A review of state‐of‐the‐Art, challenges, and opportunities for studying brain chemistry

“…Such studies have only recently become feasible. For example, in a recently reported study hybrid PET/MRI has been used to assess receptor occupancy variations and BOLD variations using different 5‐HT1a agonists, in order to evaluate whether it is possible to target different cellular pathways using molecules with similar receptor targeting‐properties, but slightly different binding which will affect molecular/pharmacological responses [Vidal et al, ].…”