Radiotracers for the Central Serotoninergic System

Mangeant, Reynald; Dubost, Emmanuelle; Cailly, Thomas

doi:10.3390/ph15050571

Cited by 3 publications

(2 citation statements)

References 298 publications

(302 reference statements)

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“…Similarly, agonists at the 5-HT2A receptor seem to label fewer binding sites than antagonists in transfected cells and are more potent in displacing agonist tracers than antagonist tracers at 5-HT2A [98], consistent with the receptor model in Figure 1. In addition, only agonist but not antagonist tracers can be detectably affected by competing levels of endogenous agonist ligands, demonstrated with serotonin in vivo load and 5-HT2A imaging with an agonist and antagonist tracer [97]. Distinct binding properties of agonists and antagonists are consistent with ligand-free R* signaling, yielding distinct in vivo labeling patterns as indicators of ligand-free R* signaling.…”

Section: Relevance Of Ligand-free R* Signaling To In Vivo Receptor Im...mentioning

confidence: 98%

“…For the interpretation of imaging studies of GPCRs with potent labeled ligands [96], the receptor model can serve to dissect agonist and antagonist binding profiles in vivo. For accurate positron emission tomography (PET) imaging of neurotransmitter receptors, for example serotonin receptors [97], a large portion of high affinity tracers present in the brain must reside at receptor sites to attain clear images. This phenomenon can result from selective retention in a receptor domain because of a diffusion boundary (for example the synaptic cleft) that slows ligand dispersal (Figure 3) [66].…”

Section: Relevance Of Ligand-free R* Signaling To In Vivo Receptor Im...mentioning

confidence: 99%

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Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

Sadee

2023

Molecules

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G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activated agonist-receptor G-protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and μ opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling—proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). The hypothesis is proposed that ligand-free signaling of 5-HT2A receptors mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close the gaps in our knowledge of ligand-free GPCR signaling.

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Section: Relevance Of Ligand-free R* Signaling To In Vivo Receptor Im...mentioning

confidence: 98%

Section: Relevance Of Ligand-free R* Signaling To In Vivo Receptor Im...mentioning

confidence: 99%

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

Sadee

2023

Molecules

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[18F]RS-127445 radiosynthesis and evaluation as a 5-HT2B receptor PET radiotracer in rat brain

Richin,

Bouillot,

Bouvard

et al. 2024

Bioorganic & Medicinal Chemistry Letters

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Ligand-Free Signaling of G Protein Coupled Receptors: Physiology, Pharmacology, and Genetics

Sadée¹

2023

Preprint

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G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activate agonist-receptor-G protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and  opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling - proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). Ligand-free signaling of intracellular 5-HT2A receptors could mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close gaps in our knowledge of ligand-free GPCR signaling.

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Radiotracers for the Central Serotoninergic System

Abstract: This review lists the most important radiotracers described so far for imaging the central serotoninergic system. Single-photon emission computed tomography and positron emission tomography radiotracers are reviewed and critically discussed for each receptor.

Cited by 3 publications

References 298 publications

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics

[18F]RS-127445 radiosynthesis and evaluation as a 5-HT2B receptor PET radiotracer in rat brain

Ligand-Free Signaling of G Protein Coupled Receptors: Physiology, Pharmacology, and Genetics

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