Publications by authors named "Luc Zimmer"

101 Publications

Neuropsychopharmacology, a challenge for the understanding of the thinking brain and its future therapies.

Authors:
Luc Zimmer Régis Bordet

Therapie 2021 Jan 23. Epub 2021 Jan 23.

Université de Lille, Inserm, CHU de Lille, 59045 Lille, France.

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http://dx.doi.org/10.1016/j.therap.2021.01.055DOI Listing
January 2021

The contrasting landscape of drug discovery in neuropsychopharmacology. A conversation with Adrian Newman-Tancredi.

Authors:
Adrian Newman-Tancredi Luc Zimmer

Therapie 2020 Dec 5. Epub 2020 Dec 5.

Lyon Neuroscience Research Centre, INSERM, CNRS, Université Claude Bernard Lyon 1, 69675 Bron, France; CERMEP, Hospices Civils de Lyon, 69500 Bron, France; National Institute for Nuclear Science and Technology, INSTN, CEA, 91400 Saclay, France. Electronic address:

For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Committee of the French Society of Pharmacology and Therapeutics (SFPT), talked with Adrian Newman-Tancredi, neuropharmacologist, co-founder and CEO of a biopharmaceutical company developing clinical-stage central nervous system drugs. They address through experiences the particularities of research in neuropsychopharmacology in the pharmaceutical industry. The evolution of drug discovery strategy is also discussed, as well as the reasons for the contrasting landscape of research for new molecules for psychiatry.
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http://dx.doi.org/10.1016/j.therap.2020.12.004DOI Listing
December 2020

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

Authors:
Oriane Razakarivony Adrian Newman-Tancredi Luc Zimmer

Transl Psychiatry 2021 01 7;11(1):22. Epub 2021 Jan 7.

Université de Lyon, Lyon Neuroscience Research Center, INSERM, CNRS, Lyon, France.

The serotonin 5-HT 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-HT radiotracers, which lack specificity and/or bind to all 5-HT 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-HT receptor it is now possible to use [F]-F13640, a 5-HT 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-HT 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-HT 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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http://dx.doi.org/10.1038/s41398-020-01119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791062PMC
January 2021

Experimental neuropsychopharmacology, yesterday, today and tomorrow. A conversation with Michel Hamon.

Authors:
Michel Hamon Luc Zimmer

Therapie 2020 Dec 5. Epub 2020 Dec 5.

Lyon Neuroscience Research Centre, INSERM, CNRS, Université Claude Bernard Lyon 1, 69675 Bron, France; CERMEP, Hospices Civils de Lyon, 69500 Bron, France; National Institute for Nuclear Science and Technology, INSTN, CEA, 91400 Saclay, France. Electronic address:

For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Committee of the French Society of Pharmacology and Therapeutics, talked with Michel Hamon, honorary director of research at the French National Institute of Health and Medical Research (INSERM) and honorary professor of neuropharmacology at Paris-Sorbonne (Pierre et Marie Curie) University. Some of the leading names in neuropsychopharmacology research are mentioned, pointing to significant conceptual advances that founded this discipline. The links between psychopharmacology and neuropharmacology are also discussed in the light of past collaborations. Finally, priorities are proposed for the emergence of the psychopharmacology of the future.
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http://dx.doi.org/10.1016/j.therap.2020.12.002DOI Listing
December 2020

Clinical research in psychopharmacology, the current situation and its perspectives. A conversation with Pierre-Michel Llorca.

Authors:
Pierre-Michel Llorca Luc Zimmer

Therapie 2020 Dec 5. Epub 2020 Dec 5.

Lyon Neuroscience Research Centre, INSERM, CNRS, Université Claude Bernard Lyon 1, 69675 Bron, France; CERMEP, Hospices Civils de Lyon, 69500 Bron, France; National Institute for Nuclear Science and Technology INSTN, CEA, 91400 Saclay, France. Electronic address:

For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Committee of the French Society of Pharmacology and Therapeutics (SFPT), talked with Michel Llorca, professor of psychiatry at the Université d'Auvergne and head of a department of psychiatry at the University Hospital of Clermond-Ferrand. They discuss together the positioning of psychiatry in the neurosciences and the need to build bridges with other medical disciplines. Through examples and professional experiences, they also talk about the difficulties of developing clinical biomarkers for psychiatry and ultimately for psychopharmacology. Finally, they discuss the current difficulties facing research of drugs for psychiatry, pointing out some success stories.
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http://dx.doi.org/10.1016/j.therap.2020.12.003DOI Listing
December 2020

Innovative approaches in CNS drug discovery.

Authors:
Mathieu Charvériat Vincent Lafon Franck Mouthon Luc Zimmer

Therapie 2020 Dec 5. Epub 2020 Dec 5.

Université de Lyon, 69675 Lyon, France; Hospices civils de Lyon, 69500 Bron, France.

Central nervous system disorders remain the leading causes of mortality and morbidity worldwide, affecting more than 1 billion patients. This therapeutic area suffers from high unmet medical needs and the search for innovative approaches to identify therapeutic strategies is urgent in the field. This review will first cover the challenges and opportunities of drug discovery in neurology, and then as well as the new models, such as human model stem cells and animal models under development in the field. In addition, innovative and translational neuroimaging techniques will be discussed, as the use of big data and artificial intelligence to discovery new drugs in neurological and neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.therap.2020.12.006DOI Listing
December 2020

Cluster headache: state of the art of pharmacological treatments and therapeutic perspectives.

Authors:
Pierre Courault Geneviève Demarquay Luc Zimmer Sophie Lancelot

Fundam Clin Pharmacol 2020 Dec 8. Epub 2020 Dec 8.

Lyon Neuroscience Research Center (CRNL), Université de Lyon, CNRS, INSERM, Lyon, France.

Cluster headache (CH) is the most common form of trigeminal autonomic cephalalgia. Current treatments have several limitations, and new drugs are required. This article first briefly reviews present acute and preventive treatments in CH, their mechanism of action and limitations, then describes the state of the art in recent clinical drug trials since 2015, and ends with a critique of trials in the CH field. Research is limited by lack of knowledge of pathophysiology and lack of animal models. In the past 5 years, no brand-new treatment has emerged, but promising drugs, such as CGRP(R) antibodies, are under study. According to the literature and guidelines, clinicians and researchers should be aware of many limitations in study protocols: concomitant medication, patient sample size, patients' protocol compliance, and study designs that tend to restrict patient recruitment.
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http://dx.doi.org/10.1111/fcp.12636DOI Listing
December 2020

Pharmaco-fUS for Characterizing Drugs for Alzheimer's Disease - The Case of THN201, a Drug Combination of Donepezil Plus Mefloquine.

Authors:
Benjamin Vidal Marine Droguerre Marco Valdebenito Luc Zimmer Michel Hamon Franck Mouthon Mathieu Charvériat

Front Neurosci 2020 12;14:835. Epub 2020 Aug 12.

Theranexus, Lyon, France.

Donepezil is a potent acetylcholinesterase inhibitor, largely used worldwide to alleviate cognitive symptoms in Alzheimer's disease (AD). Beyond the widely described neuronal impact of donepezil, it was recently shown that targeting connexins, the proteins involved in astrocyte network organization, potentiates donepezil efficacy profile using behavioral tests in AD rodent models. We herein present data demonstrating the potential of functional ultrasound imaging to monitor cerebral activity changes after pharmacological challenge in mice. As an example, we showed that although administration of donepezil or mefloquine alone at low dose had only very limited effects on the signal compared to the baseline, their combination produced marked hemodynamic effects in the hippocampus, in line with previously published behavioral data demonstrating a synergic interaction between both drugs. Thus, the present study provides new perspectives, (i) through the use of pharmaco-fUS, a new non-clinical imaging modality, to move forward drug discovery in AD and (ii) by the profiling of two drug treatments on brain dynamics, one used in AD: donepezil, and the other in development: donepezil combined with mefloquine (THN201) as a modulator of astrocyte network.
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http://dx.doi.org/10.3389/fnins.2020.00835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437134PMC
August 2020

Functional ultrasound imaging to study brain dynamics: Application of pharmaco-fUS to atomoxetine.

Authors:
Benjamin Vidal Marine Droguerre Ludovic Venet Luc Zimmer Marco Valdebenito Franck Mouthon Mathieu Charvériat

Neuropharmacology 2020 11 13;179:108273. Epub 2020 Aug 13.

Theranexus, Lyon, France.

Functional ultrasound (fUS) is a new tool enabling the imaging of brain activity through the regional monitoring of cerebral blood volume (CBV) dynamics. This innovative technique has not yet demonstrated its full potential in pharmacological applications and drug development. In the current proof-of-concept study, the impact of atomoxetine (ATX), a potent norepinephrine reuptake inhibitor and non-stimulant treatment marketed in attention-deficit/hyperactivity-disorder, was evaluated in anesthetized rat using pharmacological functional ultrasound (pharmaco-fUS) at increasing doses (0.3, 1 and 3 mg/kg). Using regions of interest (acute changes of CBV and functional connectivity) or pixel-based (general linear modeling and independent component analysis) analysis, we here demonstrated that ATX consistently displayed a hemodynamic effect in the visual cortex, the dentate gyrus and thalamus, especially visual areas such as lateral posterior thalamic nuclei and lateral geniculate nuclei (LGN). The time profile of ATX effects was dose-dependent, with fastest CBV increases at the highest dose, and longer CBV increases at the intermediate dose. Standardizing the use of pharmaco-fUS could improve our understanding of the mechanism of action of drugs active in the brain and might constitute a new step to move forward in drug development for neurological disorders.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108273DOI Listing
November 2020

Bayesian Estimation of the ntPET Model in Single-Scan Competition PET Studies.

Authors:
Zacharie Irace Inés Mérida Jérôme Redouté Clara Fonteneau Marie-Françoise Suaud-Chagny Jérôme Brunelin Benjamin Vidal Luc Zimmer Anthonin Reilhac Nicolas Costes

Front Physiol 2020 19;11:498. Epub 2020 May 19.

CERMEP-Life Imaging, Lyon, France.

This paper proposes an innovative method, named b-ntPET, for solving a competition model in PET. The model is built upon the state-of-the-art method called lp-ntPET. It consists in identifying the parameters of the PET kinetic model relative to a reference region that rule the steady state exchanges, together with the identification of four additional parameters defining a displacement curve caused by an endogenous neurotransmitter discharge, or by a competing injected drug targeting the same receptors as the PET tracer. The resolution process of lp-ntPET is however suboptimal due to the use of discretized basis functions, and is very sensitive to noise, limiting its sensitivity and accuracy. Contrary to the original method, our proposed resolution approach first estimates the probability distribution of the unknown parameters using Markov-Chain Monte-Carlo sampling, distributions from which the estimates are then inferred. In addition, and for increased robustness, the noise level is jointly estimated with the parameters of the model. Finally, the resolution is formulated in a Bayesian framework, allowing the introduction of prior knowledge on the parameters to guide the estimation process toward realistic solutions. The performance of our method was first assessed and compared head-to-head with the reference method lp-ntPET using well-controlled realistic simulated data. The results showed that the b-ntPET method is substantially more robust to noise and much more sensitive and accurate than lp-ntPET. We then applied the model to experimental animal data acquired in pharmacological challenge studies and human data with endogenous releases induced by transcranial direct current stimulation. In the drug challenge experiment on cats using [F]MPPF, a serotoninergic 1A antagonist radioligand, b-ntPET measured a dose response associated with the amount of the challenged injected concurrent 5-HT1A agonist, where lp-ntPET failed. In human [C]raclopride experiment, contrary to lp-ntPET, b-ntPET successfully detected significant endogenous dopamine releases induced by the stimulation. In conclusion, our results showed that the proposed method b-ntPET has similar performance to lp-ntPET for detecting displacements, but with higher resistance to noise and better robustness to various experimental contexts. These improvements lead to the possibility of detecting and characterizing dynamic drug occupancy from a single PET scan more efficiently.
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http://dx.doi.org/10.3389/fphys.2020.00498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248280PMC
May 2020

Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer's Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P.

Authors:
Pierre Courault Stéphane Emery Sandrine Bouvard François Liger Fabien Chauveau David Meyronet Anthony Fourier Thierry Billard Luc Zimmer Sophie Lancelot

J Alzheimers Dis 2020 ;75(4):1329-1338

Lyon Neuroscience Research Center (CRNL), Université de Lyon, CNRS, INSERM, Lyon, France.

Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders.

Objective: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages.

Methods: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15).

Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011).

Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.
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http://dx.doi.org/10.3233/JAD-191278DOI Listing
January 2020

Preclinical validation of [F]2FNQ1P as a specific PET radiotracer of 5-HT receptors in rat, pig, non-human primate and human brain tissue.

Authors:
Stéphane Emery Sylvain Fieux Benjamin Vidal Pierre Courault Sandrine Bouvard Christian Tourvieille Thibaut Iecker Thierry Billard Luc Zimmer Sophie Lancelot

Nucl Med Biol 2020 Mar - Apr;82-83:57-63. Epub 2020 Jan 22.

Lyon Neuroscience Research Center, Université de Lyon, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Bron, France; CERMEP Imaging Platform, Bron, France.

Introduction: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [F]2FNQ1P, a new PET radiotracer of 5-HT receptors, in rat, pig, non-human primate and human tissues. The 5-HT receptor is one of the more recently identified serotonin receptors in central nervous system and, because of its role in memory and cognitive processes, is considered as a promising therapeutic target.

Methods: In-vitro autoradiography and saturation binding assays were performed in postmortem brain tissues from rat, pig, non-human primate and human caudate nucleus, completed by serum stability assessment in all species and cerebral radiometabolite and biodistribution studies in rat.

Results: In all species, autoradiography data revealed high binding levels of [F]2FNQ1P in cerebral regions with high 5-HT receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided K and B values of respectively 1.34 nM and 0.03 pmol·mg in rat, 0.60 nM and 0.04 pmol·mg in pig, 1.38 nM and 0.07 pmol·mg in non-human primate, and 1.39 nM and 0.15 pmol·mg in human caudate nucleus. In rat brain, the proportion of unmetabolized [F]2FNQ1P was >99% 5 min after iv injection and 89% at 40 min. The biodistribution studies found maximal radioactivity in lungs and kidneys (3.5 ± 1.2% ID/g and 2.0 ± 0.7% ID/g, respectively, 15 min post-injection).

Conclusion: These radiopharmacological data confirm that [F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT receptors and suggest that it could be used as a radiopharmaceutical in humans.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.01.006DOI Listing
January 2020

, a Journal at the Crossroads of the Scientific and Medical Disciplines of Biomedical Imaging.

Authors:
Luc Zimmer

Contrast Media Mol Imaging 2019 9;2019:7213829. Epub 2019 Dec 9.

Université de Lyon, INSERM, CNRS, Lyon Neuroscience Research Center, Lyon, France.

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http://dx.doi.org/10.1155/2019/7213829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925829PMC
December 2019

[PET imaging for better understanding of normal and pathological neurotransmission].

Authors:
Luc Zimmer

Biol Aujourdhui 2019 12;213(3-4):109-120. Epub 2019 Dec 12.

Centre de Recherche en Neurosciences de Lyon (CNRS - INSERM - Université Claude Bernard Lyon 1), Lyon, France - CERMEP-Imagerie du Vivant, Hospices Civils de Lyon, Bron, France - Institut National des Sciences et Techniques Nucléaires, CEA, Saclay, France.

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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http://dx.doi.org/10.1051/jbio/2019025DOI Listing
May 2020

Pharmacological MRI to investigate the functional selectivity of 5-HT receptor biased agonists.

Authors:
Benjamin Vidal Radu Bolbos Jérôme Redouté Jean-Baptiste Langlois Nicolas Costes Adrian Newman-Tancredi Luc Zimmer

Neuropharmacology 2020 08 26;172:107867. Epub 2019 Nov 26.

Université de Lyon, Lyon Neuroscience Research Center, INSERM, CNRS, Bron, France; CERMEP-Imagerie du Vivant, Bron, France; Hospices Civils de Lyon, Lyon, France; National Institute for Nuclear Science and Technology, Saclay, France. Electronic address:

The emerging concept of "biased agonism" denotes the phenomenon whereby agonists can preferentially direct receptor signalling to specific intracellular responses among the different transduction pathways, thus potentially avoiding side effects and improving therapeutic effects. The aim of this study was to investigate biased agonism by using pharmacological magnetic resonance imaging (phMRI). The cerebral blood oxygen level dependent (BOLD) signal changes induced by increasing doses of two serotonin 5-HT receptor biased agonists, NLX-112 and NLX-101, were mapped in anaesthetized rats. Although both compounds display high affinity, selectivity and agonist efficacy for 5-HT receptors, NLX-101 is known to preferentially activate post-synaptic receptors, whereas NLX-112 targets both pre- and post-synaptic receptors. We used several doses of agonists in order to determine if the regional selectivity of NLX-101 was dose-dependent. NLX-112 and NLX-101 induced different positive and negative hemodynamic changes patterns at equal doses. Importantly, NLX-101 had no significant effect in regions expressing pre-synaptic receptors contrary to NLX-112. NLX-112 also produced higher BOLD changes than NLX-101 in the orbital cortex, the somatosensory cortex, and the magnocellular preoptic nuclei. In other regions such as the retrosplenial cortex and the dorsal thalamus, the drugs had similar effects. In terms of functional connectivity, NLX-112 induced more widespread changes than NLX-101. The present phMRI study demonstrates that two closely-related agonists display notable differences in their hemodynamic "fingerprints". These data support the concept of biased agonism at 5-HT receptors and raise the prospect of identifying novel therapeutics which exhibit improved targeting of brain regions implicated in neuropsychiatric disorders. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107867DOI Listing
August 2020

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

Authors:
Matthieu Colom Benjamin Vidal Luc Zimmer

Front Mol Neurosci 2019 18;12:255. Epub 2019 Oct 18.

Lyon Neuroscience Research Center, INSERM, CNRS, Université de Lyon, Lyon, France.

Positron emission tomography (PET) is a molecular imaging modality that enables 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. 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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http://dx.doi.org/10.3389/fnmol.2019.00255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813225PMC
October 2019

F-F13640 PET imaging of functional receptors in humans.

Authors:
Matthieu Colom Nicolas Costes Jérôme Redouté Frédéric Dailler Florent Gobert Didier Le Bars Thierry Billard Adrian Newman-Tancredi Luc Zimmer

Eur J Nucl Med Mol Imaging 2020 01 14;47(1):220-221. Epub 2019 Aug 14.

Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.1007/s00259-019-04473-7DOI Listing
January 2020

Evaluation of Myelin Radiotracers in the Lysolecithin Rat Model of Focal Demyelination: Beware of Pitfalls!

Authors:
Min Zhang Gaëlle Hugon Caroline Bouillot Radu Bolbos Jean-Baptiste Langlois Thierry Billard Frédéric Bonnefoi Biao Li Luc Zimmer Fabien Chauveau

Contrast Media Mol Imaging 2019 29;2019:9294586. Epub 2019 May 29.

University of Lyon, Lyon Neuroscience Research Center (CRNL), Lyon, France.

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [C]PIB was used to show that PET does not provide sufficient sensitivity to reliably track myelin changes and may be sensitive to LPC side effects instead of demyelination as such. autoradiography with a fluorine radiotracer should be preferred, to adequately evaluate and compare radiotracers for the assessment of myelin content.
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http://dx.doi.org/10.1155/2019/9294586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594279PMC
July 2020

Serotonin 5-HT Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats.

Authors:
Elise Levigoureux Benjamin Vidal Sylvain Fieux Caroline Bouillot Stéphane Emery Adrian Newman-Tancredi Luc Zimmer

ACS Chem Neurosci 2019 07 7;10(7):3108-3119. Epub 2019 Jan 7.

Université de Lyon, Université Claude Bernard Lyon 1 , Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028 , Lyon 69677 , France.

Serotonin 5-HT receptors constitute an attractive therapeutic target for various psychiatric or neurodegenerative disorders. These receptors are expressed in multiple brain regions on different neuronal populations and can be coupled with distinct G-protein subtypes; such functional diversity complicates the use of 5-HT ligands in several pathologies where it would be desirable to stimulate the receptors in a precise region. Therefore, using "biased agonists" able to target specifically certain subpopulations of 5-HT receptors would enable achievement of better therapeutic benefit. Several 5-HT receptor biased agonists are currently in development, including NLX-101 (aka F15599) and NLX-112 (aka F13640, befiradol), with preclinical data suggesting that they preferentially target different populations of 5-HT receptors. However, most previous studies used invasive and regionally limited approaches. In this context, [F]-fluorodesoxyglucose (FDG)-positron emission tomography (PET) imaging constitutes an interesting technique as it enables noninvasive mapping of the regional brain activity changes following a pharmacological challenge in conscious animals. We report here the evaluation of cerebral glucose metabolism following intraperitoneal injection of different doses of NLX-112 or NLX-101 in conscious or isoflurane-anesthetized rats. The biased agonists produced different metabolic "fingerprints" with distinct regional preferences, consistent with previous studies. At equal doses, the effect of NLX-101 was less marked than NLX-112 in the piriform cortex, in the striatum (in terms of inhibition), and in the pontine nuclei and the cerebellum (in terms of activation); furthermore, only NLX-112 increased the glucose metabolism in the parietal cortex, whereas only NLX-101 induced a clear activation in the colliculi and the frontal cortex, which may be related to its distinctive procognitive profile. Both agonist effects were almost completely unapparent in anesthetized animals, underlining the importance of studying serotonergic neurotransmission in the conscious state. In this regard, [F]FDG-PET imaging seems very complementary with other functional imaging techniques such as pharmacological MRI.
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http://dx.doi.org/10.1021/acschemneuro.8b00584DOI Listing
July 2019

Evaluation of [ F]2FP3 in pigs and non-human primates.

Authors:
Hanne D Hansen Cristian C Constantinescu Olivier Barret Matthias M Herth Janus H Magnussen Szabolcs Lehel Agnete Dyssegaard Julie Colomb Thierry Billard Luc Zimmer Gilles Tamagnan Gitte M Knudsen

J Labelled Comp Radiopharm 2019 01 6;62(1):34-42. Epub 2018 Dec 6.

Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

So far, no suitable 5-HT R radioligand exists for clinical positron emission tomography (PET) imaging. [ F]2FP3 was first tested in vivo in cats, and the results were promising for further evaluations. Here, we evaluate the radioligand in pigs and non-human primates (NHPs). Furthermore, we investigate species differences in 5-HT R binding with [ H]SB-269970 autoradiography in post-mortem pig, NHP, and human brain tissue. Specific binding of [ F]2FP3 was investigated by intravenous administration of the 5-HT R specific antagonist SB-269970. [ H]SB-269970 autoradiography was performed as previously described. [ F]2FP3 was synthesized in an overall yield of 35% to 45%. High brain uptake of the tracer was found in both pigs and NHPs; however, pretreatment with SB-269970 only resulted in decreased binding of 20% in the thalamus, a 5-HT R-rich region. Autoradiography on post-mortem pig, NHP, and human tissues revealed that specific binding of [ H]SB-269970 was comparable in the thalamus of pig and NHP. Despite the high uptake of [ F]2FP3 in both species, the binding could only be blocked to a limited degree with the 5-HT R antagonists. We speculate that the affinity of the radioligand is too low for imaging the 5-HT Rs in vivo and that part of the PET signal arises from targets other than the 5-HT R.
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http://dx.doi.org/10.1002/jlcr.3692DOI Listing
January 2019

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

Authors:
Benjamin Vidal Sylvain Fieux Jérôme Redouté Marjorie Villien Frédéric Bonnefoi Didier Le Bars Adrian Newman-Tancredi Nicolas Costes Luc Zimmer

Neuropsychopharmacology 2018 10 6;43(11):2310-2319. Epub 2018 Jul 6.

Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, INSERM, CNRS, 69500, Bron, France.

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.
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http://dx.doi.org/10.1038/s41386-018-0145-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135772PMC
October 2018

In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging.

Authors:
Mathieu Verdurand Elise Levigoureux Wael Zeinyeh Laurent Berthier Meriem Mendjel-Herda Florence Cadarossanesaib Caroline Bouillot Thibault Iecker Raphaël Terreux Sophie Lancelot Fabien Chauveau Thierry Billard Luc Zimmer

Mol Pharm 2018 08 25;15(8):3153-3166. Epub 2018 Jul 25.

Université de Lyon, Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028 , Lyon 69361 , France.

Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aβ fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00229DOI Listing
August 2018

PET imaging of the influence of physiological and pathological α-synuclein on dopaminergic and serotonergic neurotransmission in mouse models.

Authors:
Elise Levigoureux Caroline Bouillot Thierry Baron Luc Zimmer Sophie Lancelot

CNS Neurosci Ther 2019 01 20;25(1):57-68. Epub 2018 May 20.

Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.

Aims: Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of neurodegenerative synucleinopathies. This in vivo study explored glucose metabolism and dopaminergic and serotoninergic neurotransmission in KO α-syn, wild-type mice and an accelerated murine model of synucleinopathy (M83).

Methods: MicroPET acquisitions were performed in all animals aged 5-6 months using five radiotracers exploring brain glucose metabolism ([ F]FDG), dopamine neurotransmission ([ C]raclopride, [ C]PE2I) and serotonin neurotransmission ([ F]MPPF, [ C]DASB). For all radiotracers, except [ F]FDG, PET data were analyzed with a MRI-based VOI method and a voxel-based analysis.

Results: MicroPET data showed a decrease in [ C]raclopride uptake in the caudate putamen of KO α-syn mice, in comparison with M83 and WT mice, reflecting a lower concentration of D receptors. The increase in [ F]MPPF uptake in M83 vs WT and KO mice indicates overexpression of 5-HT receptors. The lack of change in dopamine and serotonin transporters in all groups suggests unchanged neuronal density.

Conclusions: This PET study highlights an effect of α-syn modulation on the expression of the D receptor, whereas aggregated α-syn leads to overexpression of 5-HT receptor, as a pathophysiological signature.
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http://dx.doi.org/10.1111/cns.12978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436587PMC
January 2019

F-F13640 preclinical evaluation in rodent, cat and primate as a 5-HT receptor agonist for PET neuroimaging.

Authors:
Benjamin Vidal Sylvain Fieux Matthieu Colom Thierry Billard Caroline Bouillot Olivier Barret Cristian Constantinescu Gilles Tamagnan Adrian Newman-Tancredi Luc Zimmer

Brain Struct Funct 2018 Jul 5;223(6):2973-2988. Epub 2018 May 5.

Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, INSERM, CNRS, Lyon, France.

Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerative disorders. Currently, all available 5-HT receptor PET radiopharmaceuticals that are radiolabeled with fluorine-18 are antagonists. As agonists bind preferentially to the high-affinity state of receptors, it would be of great interest to develop agonist radioligands which could provide a measure of the functional 5-HT receptors in pathophysiological processes. The 5-HT receptor agonist candidates we recently proposed had promising in vitro properties but were not optimal in terms of PET imaging. F13640, a.k.a befiradol or NLX-112, is a 5-HT receptor agonist with a high affinity (Ki = 1 nM) and a high selectivity that would be suitable for a potential PET radiopharmaceutical. With propose here the first preclinical evaluation of F-F13640. F-F13640's nitro-precursor was synthesized and radiolabeled via a fluoro-nucleophilic substitution. Its radiopharmacological characterization included autoradiographic studies, metabolic studies, and in vivo PET scans in rat, cat and non-human primate. Some of the results were compared with the radiotracer F-MPPF, a 5-HT receptor antagonist. The radiochemical purity of F-F13640 was > 98%. In vitro binding pattern was consistent with the 5-HT receptor distribution. Metabolic studies revealed that the radiotracer rapidly entered the brain and led to few brain radiometabolites. Although F-F13640 in vivo binding was blocked by the 5-HT antagonist WAY-100635 and the 5-HT agonist 8-OH-DPAT, the distribution pattern was markedly different from antagonist radiotracers in the three species, suggesting it provides novel information on 5-HT receptors. Preliminary studies also suggest a high sensitivity of F-F13640 to endogenous serotonin release. F-F13640 has suitable characteristics for probing in vitro and in vivo the 5-HT receptors in high-affinity state. Quantification analyses with kinetic modeling are in progress to prepare the first-in-man study of F-F13640.
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http://dx.doi.org/10.1007/s00429-018-1672-7DOI Listing
July 2018

Amyloid-Beta Radiotracer [F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy Brain Tissue.

Authors:
Mathieu Verdurand Elise Levigoureux Sophie Lancelot Waël Zeinyeh Thierry Billard Isabelle Quadrio Armand Perret-Liaudet Luc Zimmer Fabien Chauveau

Contrast Media Mol Imaging 2018 6;2018:9165458. Epub 2018 Feb 6.

Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.

The accumulation of aggregated alpha-synuclein (-syn) in multiple brain regions is a neuropathological hallmark of synucleinopathies. Multiple system atrophy (MSA) is a synucleinopathy characterized by the predominant cerebral accumulation of aggregated -syn as cytoplasmic glial inclusions (CGI). A premortem diagnosis tool would improve early diagnosis and help monitoring disease progression and therapeutic efficacy. One Positron Emission Tomography (PET) study suggested [C]BF-227 as a promising radiotracer for monitoring intracellular -syn deposition in MSA patients. We sought to confirm the binding of this radiotracer to -syn using state-of-the-art autoradiography. Medulla sections were obtained from 9 MSA patients and 9 controls (London Neurodegenerative Diseases Brain Bank). [F]BF-227, chemically identical to [C]BF-227, was used at nanomolar concentrations to perform autoradiography assays. Autoradiograms were superimposed on fluorescent staining from the conformational anti--syn antibody 5G4 and quantified after immunofluorescence-driven definition of regions of interest. Autoradiography showed no specific signals in MSA patients in comparison to controls despite widespread pathology detected by immunofluorescence. Autoradiography does not support a significant binding of [F]BF-227 to CGI at concentrations typically achieved in PET experiments.
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http://dx.doi.org/10.1155/2018/9165458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818909PMC
July 2019

Ozone Atmospheric Pollution and Alzheimer's Disease: From Epidemiological Facts to Molecular Mechanisms.

Authors:
Marine L Croze Luc Zimmer

J Alzheimers Dis 2018 ;62(2):503-522

Université Claude Bernard Lyon 1, INSERM, CNRS, Lyon Neuroscience Research Center, Lyon, France.

Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer's disease (AD). The focus of this review is to highlight the possible link between ozone air pollution exposure and AD incidence. This review's approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated.
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http://dx.doi.org/10.3233/JAD-170857DOI Listing
February 2019

The in Vitro Actions of Loxapine on Dopaminergic and Serotonergic Receptors. Time to Consider Atypical Classification of This Antipsychotic Drug?

Authors:
Florian Ferreri Dominique Drapier Emmanuelle Baloche Mehemed Ouzid Luc Zimmer Pierre-Michel Llorca

Int J Neuropsychopharmacol 2018 04;21(4):355-360

CMP B, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Background: The denomination of typical antipsychotic for loxapine has poor relation to current knowledge of the molecule's relevant modes of action.

Materials And Methods: Competition binding experiments were performed on expressed human recombinant receptors in CHO cells and HEK-293 cells for D1 to D5, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT4, 5-HT6, and 5-HT7. In vitro autoradiographies using [11C]-Raclopride [18F]-Altanserin [18F]-MPPF [11C]-SB207145, and [18F]-2FNQ1P were measured in brain tissue of a male primate followed by addition of increasing doses of loxapine succinate.

Results: In cell cultures, the measured Kb confirmed high affinity of loxapine for the D2; intermediate affinity for the D1, D4, D5, 5-HT2C receptorsl and a lack of affinity toward D3, 5-HT1A, 5-HT4, 5-HT6, and 5-HT7 receptors. In brain tissue, PET autoradiographies showed a radiopharmaceutical displacement at low concentrations of loxapine on D2 and 5-HT2A receptors.

Conclusion: This preclinical study reveals that loxapine receptorial spectrum is close to an "atypical" profile (D2/5HT2A ratio, 1.14). Loxapine is rightly classified as a DS-RAn agent in the Neuroscience Based Nomenclature classification.
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http://dx.doi.org/10.1093/ijnp/pyx102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887516PMC
April 2018

[C]PF-3274167 as a PET radiotracer of oxytocin receptors: Radiosynthesis and evaluation in rat brain.

Authors:
Benjamin Vidal Iuliia A Karpenko François Liger Sylvain Fieux Caroline Bouillot Thierry Billard Marcel Hibert Luc Zimmer

Nucl Med Biol 2017 Dec 2;55:1-6. Epub 2017 Aug 2.

Université de Lyon, Université Claude Bernard Lyon 1, INSERM, CNRS, LabEx PRIMES, Lyon Neuroscience Research Center, Lyon, France; CERMEP-Imagerie du Vivant, Bron, France; Hospices Civils de Lyon, Lyon, France. Electronic address:

Introduction: Oxytocin plays a major role in the regulation of social interactions in mammals by interacting with the oxytocin receptor (OTR) expressed in the brain. Furthermore, the oxytocin system appears as a possible therapeutic target in autism spectrum disorders and other psychiatric troubles, justifying current pharmacological researches. Since no specific PET radioligand is currently available to image OTR in the brain, the aim of this study was to radiolabel the specific OTR antagonist PF-3274167 and to evaluate [C]PF-3274167 as a potential PET tracer for OTR in rat brains.

Methods: [C]PF-3274167 was prepared via the O-methylation of its desmethyl precursor with [C]methyl iodide. The lipophilicity of the radioactive compound was evaluated by measuring the n-octanol-buffer partition coefficient (logD). Autoradiography experiments were performed on rat brain tissue to evaluate the in vitro distribution of the [C]PF-3274167. MicroPET experiments were conducted with and without pre-injection of ciclosporin in order to evaluate the influence of the P-glycoprotein (P-gp) on the brain uptake.

Results: [C]PF-3274167 was synthesized with high radiochemical and chemical purities (>95%) and good specific activity. The measured logD was 1.93. In vitro, [C]PF-3274167 did not show any evidence of specific binding to OTR. PET imaging showed that [C]PF-3274167 uptake in rat brain was very low in basal conditions but increased significantly after the administration of ciclosporin, suggesting that it is a substrate of the P-gp. In the ciclosporin-pre-injected rat, however, [C]PF-3274167 distribution did not match with the known distribution of OTR in rats.

Conclusion: [C]PF-3274167 is not a suitable tracer for imaging of OTR in rat brain, probably because of a too low affinity for this receptor in addition to a poor brain penetration.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.07.008DOI Listing
December 2017

Characterization and Reliability of [F]2FNQ1P in Cynomolgus Monkeys as a PET Radiotracer for Serotonin 5-HT Receptors.

Authors:
Véronique Sgambato-Faure Thierry Billard Elise Météreau Sandra Duperrier Sylvain Fieux Nicolas Costes Léon Tremblay Luc Zimmer

Front Pharmacol 2017 18;8:471. Epub 2017 Jul 18.

Université Claude Bernard Lyon ILyon, France.

Brain serotonin-6 receptor (5-HTR) is the one of the most recently identified serotonin receptors. Accumulating evidence suggests that it is a potent therapeutic target for psychiatric and neurological diseases. Since [F]2FNQ1P was recently proposed as the first fluorinated positron emission tomography (PET) radioligand for this receptor, the objective of the present study was to demonstrate its suitability for 5-HTR neuroimaging in primates. [F]2FNQ1P was characterized by autoradiography and PET imaging in cynomolgus monkeys. Following PET imaging, tracer binding indices were computed using the simplified reference tissue model and Logan graphical model, with cerebellum as reference region. The tracer binding reproducibility was assessed by test-retest in five animals. Finally, specificity was assessed by pre-injection of a 5-HTR antagonist, SB258585. results showed wide cerebral distribution of the tracer with specificity toward 5-HTRs as binding was effectively displaced by SB258585. brain penetration was good with reproducible distribution at cortical and subcortical levels. The automated method gave the best spatial normalization. The Logan graphical model showed the best tracer binding indices, giving the highest magnitude, lowest standard deviation and best reproducibility and robustness. Finally, 5-HTR antagonist pre-injection significantly decreased [F]2FNQ1P binding mainly in the striatum and sensorimotor cortex. Taken together, these preclinical results show that [F]2FNQ1P is a good candidate to address 5-HT6 receptors in clinical studies.
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http://dx.doi.org/10.3389/fphar.2017.00471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513908PMC
July 2017

Hippocampal 5-HT receptor expression changes in prodromal stages of Alzheimer's disease: Beneficial or deleterious?

Authors:
Mathieu Verdurand Luc Zimmer

Neuropharmacology 2017 Sep 21;123:446-454. Epub 2017 Jun 21.

Université Claude Bernard Lyon 1, CNRS, INSERM, Lyon Neuroscience Research Center, Lyon, France; CERMEP, Hospices Civils de Lyon, Lyon, France. Electronic address:

There is increasing evidence that the serotonergic system is highly dysfunctional in Alzheimer's disease (AD), and this could be related to cognitive impairments associated with dementia. Of the various serotonin receptors, 5-HT receptors are relevant to AD as they are highly expressed in the human hippocampus and are known to be involved in the regulation of memory processes. This review will discuss the involvement of 5-HT receptors in AD at several levels (post-mortem, in-vivo imaging, animal models). The involvement of this receptor subtype in AD pathophysiology will be reviewed particularly in terms of the modulation of its expression in the hippocampal region. Hypotheses involving 5-HT receptors will be developed, from two points of view: 5-HT receptors expression regulation as being beneficial and needing to be pharmacologically stimulated; and 5-HT receptors expression modulation as deleterious and needing to be limited. Finally, we will propose perspectives for future experiments that should weigh in favor of one or the other of the two hypotheses.
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http://dx.doi.org/10.1016/j.neuropharm.2017.06.021DOI Listing
September 2017