Pharmacological agonists for more-targeted CNS radio-pharmaceuticals

Zimmer, Luc

doi:10.18632/oncotarget.13418

Cited by 9 publications

(8 citation statements)

References 7 publications

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“…The vast majority of PET radiopharmaceuticals currently used for receptor neuroimaging are antagonists. However, about 30 agonists have been used for PET imaging of various G-protein-coupled receptors: adrenergic, dopaminergic, serotonergic, muscarinic, cannabinoid, and opioid receptors [55][56][57] . Among them, a dozen of PET agonist radiotracers were developed and translated to humans for these receptors, but very few studies [58][59][60] directly compared the in vivo density of receptors targeted by an agonist versus an antagonist radiotracer in the same subject (in these cases, animal models).…”

Section: The Concept Of Functionally Active 5-ht 1a Receptor Imagingmentioning

confidence: 99%

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

2021

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The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to subjects’ pathophysiological or pharmacological state. We therefore propose imaging protocols to follow changes in the pattern of functional 5-HT1A receptors in relation to mood deficits or cognitive processes. This could allow improved discrimination of different schizophrenia phenotypes and greater understanding of the basis of therapeutic responses to antipsychotic drugs. Finally, as well as targeting functionally active receptors to gain insights into the role of 5-HT1A receptors, the concept can also be extended to the study of other receptors involved in the pathophysiology or therapy of psychiatric disorders.

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Section: The Concept Of Functionally Active 5-ht 1a Receptor Imagingmentioning

confidence: 99%

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

2021

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“…Ainsi, la comparaison, en TEP, de la liaison in vivo de l'antagoniste et de celle de l'agoniste pourrait fournir un moyen d'imagerie « fonctionnelle » des récepteurs de neurotransmetteurs (Zimmer, 2016). Le principe proposé est que les agonistes se lient préférentiellement aux récepteurs qui sont couplés aux protéines G, tandis que les antagonistes se fixent sur toute la population de récepteurs, qu'ils soient ou non couplés aux protéines G (Mongeau et al, 1992 ;Nénonéné et al, 1994).…”

Section: Vers Une Imagerie Des Récepteurs Fonctionnels ?unclassified

L’imagerie TEP pour une meilleure compréhension de la neurotransmission normale et pathologique

Zimmer

2019

Biologie Aujourd’hui

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Reçu le 17 septembre 2019Résumé --La neuroimagerie des récepteurs cérébraux a commencé au début des années 1980. Aujourd'hui, quelque quarante ans plus tard, l'imagerie par tomographie d'émission de positons (TEP) est toujours un domaine en expansion dans les études précliniques et cliniques cherchant à explorer le cerveau et son fonctionnement normal et pathologique. Outre les améliorations apportées aux caméras TEP et à l'analyse d'images, la disponibilité de radiotraceurs est un facteur déterminant de cette expansion. De nombreux radiotraceurs (ou radiopharmaceutiques, lorsque injectés chez l'Homme) ont été mis au point par des équipes pluridisciplinaires pour visualiser et quantifier un nombre croissant de récepteurs, transporteurs, enzymes et autres cibles moléculaires du cerveau. Le développement de nouveaux radiotraceurs TEP représente un défi passionnant, du fait du grand nombre de cibles et de fonctions neurochimiques qui restent encore à explorer. Dans cet article, nous resituons le contexte de développement des premiers radiotraceurs précliniques et leur passage à l'Homme. Les principales contributions actuelles des radiotraceurs TEP sont décrites en termes d'imagerie du métabolisme neuronal, de quantification des récepteurs et des transporteurs, d'imagerie neurodégénérative et neuroinflammatoire. Les différentes approches d'imagerie fonctionnelle de la neurotransmission sont également abordées. Enfin, les apports de l'imagerie TEP à la recherche et au développement de nouveaux médicaments du cerveau sont décrits. Mots clés : tomographie par émission de positons, radiopharmaceutiques, imagerie cérébrale, pharmacologieAbstract --PET imaging for better understanding of normal and pathological neurotransmission. Positron emission tomography imaging is still an expanding field of preclinical and clinical investigations exploring the brain and its normal and pathological functions. In addition to technological improvements in PET scanners, the availability of suitable radiotracers for unexplored pharmacological targets is a key factor in this expansion. Many radiotracers (or radiopharmaceuticals, when administered to humans) have been developed by multidisciplinary teams to visualize and quantify a growing numbers of brain receptors, transporters, enzymes and other targets. The development of new PET radiotracers still represents an exciting challenge, given the large number of neurochemical functions that remain to be explored. In this article, we review the development context of the first preclinical radiotracers and their passage to humans. The main current contributions of PET radiotracers are described in terms of imaging neuronal metabolism, quantification of receptors and transporters, neurodegenerative and neuroinflammatory imaging. The different approaches to functional imaging of neurotransmission are also discussed. Finally, the contributions of PET imaging to the research and development of new brain drugs are described.

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“…They seem to be involved in GPCR activity and reflect the responsiveness of the synapse signaling system (Shalgunov, 2017). Therefore, agonist radioligands could provide precise in vivo pharmacology by imaging only active neuroreceptors (Zimmer, 2016). PET would thus seem to be the means to shed light on GPCR properties in vivo .…”

Section: Introductionmentioning

confidence: 99%

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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Pharmacological agonists for more-targeted CNS radio-pharmaceuticals

Cited by 9 publications

References 7 publications

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

L’imagerie TEP pour une meilleure compréhension de la neurotransmission normale et pathologique

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

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