Influence of agonist induced internalization on [<sup>3</sup>H]Ro15‐4513 binding—an application to imaging fluctuations in endogenous GABA with positron emission tomography

Quelch, Darren; Santis, Vittorio De; Strege, Annette; Myers, Jim; Wells, Lisa; Nutt, David; Lingford‐Hughes, Anne; Parker, Christine A.; Tyacke, Robin J.

doi:10.1002/syn.21780

Cited by 8 publications

(5 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Briefly, variations in the neurotransmitter, especially increasing levels in the synapse, can influence receptor crossing from cell surface to intracellular compartment. This has been demonstrated for dopamine, serotonin (Riad et al, 2001), muscarinic (Keith et al, 1998) mu opioid receptors (Quelch et al, 2014), and α 2 receptors (Olli-Lähdesmäki et al, 1999). This adaptive process can interfere with the binding of agonist radiotracers, especially in pharmacological challenge, which induces a massive release of neurotransmitter into the synapse.…”

Section: What Is Different With Antagonist Radiotracers?mentioning

confidence: 85%

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

Colom

Vidal

Zimmer

2019

Front. Mol. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

Section: What Is Different With Antagonist Radiotracers?mentioning

confidence: 85%

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

Colom

Vidal

Zimmer

2019

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…It is therefore important to understand effects of the physiological environment on the binding of a radioligand to a receptor. In vitro studies using native brain tissue or cell lines have provided understanding of the effect of cellular location on radioligand affinity to dopamine D 2 receptors (Guo et al 2010 ; Quelch et al 2014b ; Skinbjerg et al 2009 ; Sun et al 2003 ), SERT (Quelch et al 2012 ), opioid receptors (Quelch et al 2014a ), and GABA A receptors (Quelch et al 2015 ). Alterations in the ability to bind internalized receptors may thus be a characteristic of a radioligand which could be evaluated to understand if the radioligand will be sensitive to neurotransmitter release.…”

Section: Considerations and Current Challengesmentioning

confidence: 99%

Application of cross-species PET imaging to assess neurotransmitter release in brain

et al. 2015

View full text Add to dashboard Cite

RationaleThis review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain.ObjectivesAlthough PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) “Novel Methods leading to New Medications in Depression and Schizophrenia” (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, “Cross-species and neurochemical imaging (PET) methods for drug discovery”, commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain.ResultsSharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions.ConclusionsPET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.

show abstract

“…16 [ 11 C]Ro15-4513 and [ 3 H]Ro15-4513 were used in in vitro studies of rat brain tissue to investigate the effects of vigabatrin, tiagabine, and SNAP-5114 on receptor agonist distribution. 18 …”

Section: γ-Aminobutyric Acid-benzodiazapine Receptormentioning

confidence: 99%

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Kassenbrock¹,

Vasdev²,

Liang

2016

CTMC

View full text Add to dashboard Cite

Positron emission tomography (PET) neuroimaging of ion channel linked receptors is a developing area of preclinical and clinical research. The present review focuses on recent advances with radiochemistry, preclinical and clinical PET imaging studies of three receptors that are actively pursued in neuropsychiatric drug discovery: namely the γ-aminobutyric acid-benzodiazapine (GABA) receptor, nicotinic acetylcholine receptor (nAChR), and N-methyl-d-aspartate (NMDA) receptor. Recent efforts to develop new PET radioligands for these targets with improved brain uptake, selectivity, stability and pharmacokinetics are highlighted.

show abstract

Influence of agonist induced internalization on [³H]Ro15‐4513 binding—an application to imaging fluctuations in endogenous GABA with positron emission tomography

Cited by 8 publications

References 48 publications

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

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

Application of cross-species PET imaging to assess neurotransmitter release in brain

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Contact Info

Product

Resources

About

Influence of agonist induced internalization on [3H]Ro15‐4513 binding—an application to imaging fluctuations in endogenous GABA with positron emission tomography

Cited by 8 publications

References 48 publications

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

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

Application of cross-species PET imaging to assess neurotransmitter release in brain

Selected PET Radioligands for Ion Channel Linked Neuroreceptor Imaging: Focus on GABA, NMDA and nACh Receptors

Contact Info

Product

Resources

About

Influence of agonist induced internalization on [³H]Ro15‐4513 binding—an application to imaging fluctuations in endogenous GABA with positron emission tomography