Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging

Shalgunov, Vladimir; Waarde, Aren van; Booij, Jan; Michel, Martin C.; Dierckx, Rudi; Elsinga, Philip H.

doi:10.1002/med.21552

Cited by 21 publications

(17 citation statements)

References 222 publications

(228 reference statements)

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“…Classical receptor binding assay studies have demonstrated that 5-HT 2A R (and other GPCRs) exist in two affinity states, a high- and a low- affinity state [ 23 , 24 , 25 ]. The affinity states of the receptors are considered to represent different functional states of the receptor, high-affinity being functionally active (activation of G αi1 -protein pathway) in contrast to the low-affinity state (activation of canonical G αq/11 -protein pathway) [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

Raval

Johansen

Donovan

et al. 2021

IJMS

140

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A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.

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Section: Introductionmentioning

confidence: 99%

A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

Raval

Johansen

Donovan

et al. 2021

IJMS

140

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“…In vitro, however, [ 3 H] [Dmt 1 ]DALDA is not sensitive to sodium ions or Gpp(NH)p alone, and can bind to antagonist as well as agonist states of μ opioid receptors [31]. These are important considerations for potential imaging radioligands, since agonists typically bind only a small fraction of the receptor conformations available [54][55][56]. [Dmt 1 ]DALDA pharmacology is almost unique among μ opioid receptor agonists, but another prominent exception is [ 11 C]carfentanil, a full agonist of μ opioid receptors, which displays a low sodium effect that contributes to its suitability for brain imaging [57,58].…”

Section: Discussionmentioning

confidence: 99%

Design, synthesis and evaluation of 111In labeled DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors

Lever

Fergason-Cantrell

Carmack

et al. 2019

Nuclear Medicine and Biology

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Introduction-Peripheral mu (μ) opioid receptors are implicated in pain, bowel dysfunction and the progression of certain cancers. In an effort to identify radioligands well suited for imaging these peripheral sites, we have prepared and evaluated four hydrophilic [ 111 In]-labeled, DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated μ tetrapeptides. Methods-Peptides were prepared by solid-phase techniques, using orthogonal strategies to achieve branching to DOTA, and then characterized by HPLC, mass spectroscopy and amino acid analysis. Scaffolds included novel peptide H-Dmt-D-Ala-Phe-Orn-NH 2 (DAPO), where Dmt = 2´, 6´-dimethyltyrosine, and known peptide H-Dmt-D-Arg-Phe-Lys-NH 2 ([Dmt 1 ]DALDA). Constructs had DOTA conjugation at the Orn 4 or Lys 4 side chains, or to the C-terminal through a hexanoic acid-lysine linker. Indium(III) complexation and [ 111 In]-radiolabeling were accomplished by standard methods. Protein binding and Log D 7.4 were determined. Binding and pharmacological profiles were obtained in vitro. Biodistribution and radiometabolite studies were conducted using male CD-1 mice. Results-All four indium(III)-DOTA conjugates derived from DAPO and [Dmt 1 ]DALDA showed good selectivity and subnanomolar affinity for μ opioid receptors. One radioligand, H-Dmt-D-Ala-Phe-Orn(δ-[ 111 In]DOTA)-NH 2 , showed 25% specific binding in vivo to μ sites in mouse gut. Notably, this was the least polar of the series, and also showed low sensitivity to modulation of binding by sodium ions. All radioligands showed high kidney uptake of radiometabolites.

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“…While antagonists bind to receptors with a single affinity, agonists show two different affinities: high affinity for receptors coupled to G-proteins, and low affinity for uncoupled receptors (Figure 1). As reviewed recently (Shalgunov et al, 2019), these findings were demonstrated for various GPCRs: adrenergic (Hoffman and Lefkowitz, 1980), dopaminergic (Sibley et al, 1982; Leff et al, 1985), serotonergic (Battaglia et al, 1984; Gozlan et al, 1995; Watson et al, 2000) muscarinic (Ehlert, 1985), cannabinoid (Gullapalli et al, 2010), and opioid receptors (Law et al, 1985). The pharmacology of high-affinity receptors features specific phenomena: negative GTP cycle feedback loop, oligo-heterodimerization, internalization.…”

Section: Introductionmentioning

confidence: 87%

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

Colom

Vidal

Zimmer

2019

Front. Mol. Neurosci.

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Positron emission tomography (PET) is a molecular imaging modality that enables in vivo exploration of metabolic processes and especially the pharmacology of neuroreceptors. G protein-coupled receptors (GPCRs) play an important role in numerous pathophysiologic disorders of the central nervous system. Thus, they are targets of choice in PET imaging to bring proof concept of change in density in pathological conditions or in pharmacological challenge. At present, most radiotracers are antagonist ligands. In vitro data suggest that properties differ between GPCR agonists and antagonists: antagonists bind to receptors with a single affinity, whereas agonists are characterized by two different affinities: high affinity for receptors that undergo functional coupling to G-proteins, and low affinity for those that are not coupled. In this context, agonist radiotracers may be useful tools to give functional images of GPCRs in the brain, with high sensitivity to neurotransmitter release. Here, we review all existing PET radiotracers used from animals to humans and their role for understanding the ligand-receptor paradigm of GPCR in comparison with corresponding antagonist radiotracers.

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Hunting for the high‐affinity state of G‐protein‐coupled receptors with agonist tracers: Theoretical and practical considerations for positron emission tomography imaging

Cited by 21 publications

References 222 publications

A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

Design, synthesis and evaluation of 111In labeled DOTA-conjugated tetrapeptides having high affinity and selectivity for mu opioid receptors

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

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