Publications by authors named "Mathieu Verdurand"

21 Publications

  • Page 1 of 1

A multicenter cohort study to investigate the factors associated with functional autonomy change in patients with cognitive complaint or neurocognitive disorders: the MEMORA study protocol.

BMC Geriatr 2019 07 18;19(1):191. Epub 2019 Jul 18.

Centre Mémoire Ressource et Recherche de Lyon (CMRR), Hôpital des Charpennes, Hospices Civils de Lyon, Lyon, France.

Background: The identification of factors associated with functional impairment, in particular those which are potentially modifiable, may help to delay the advanced stages of functional dependence in patients with neurocognitive disorders such as Alzheimer's disease and related disorders. The objectives of the MEMORA cohort are to investigate the factors associated, first with functional autonomy change over time, and secondarily with the cognitive performance and behavioral disorders changes over time.

Methods: The MEMORA study is a multicenter prospective cohort study carried out throughout the patient's care pathway, in Memory centers of Lyon (France). The study will include 6780 patients at all stages of memory disorders in 6 years. The follow-up for each patient is planned for 3 years. The main outcome is the functional autonomy level change as assessed by the instrumental abilities of daily living (IADL) score. Patient characteristics include sociodemographic and clinical features, neuropsychological performance, pharmaceutical and non-pharmaceutical therapy.

Discussion: This study conducted in a context of routine care may help to identify the factors associated with functional impairment related to progressive neurocognitive disorders. Subsequently, interventions on potentially modifiable factors could be proposed to the patients to improve their management and delay functional dependence.

Trial Registration: NCT02302482 , registered 27 November 2014.
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http://dx.doi.org/10.1186/s12877-019-1204-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637582PMC
July 2019

Impact of Cognitive, Functional, Behavioral Disorders, and Caregiver Burden on the Risk of Nursing Home Placement.

J Am Med Dir Assoc 2019 10 17;20(10):1254-1262. Epub 2019 May 17.

Clinical and Research Memory Centre of Lyon (CMRR), Geriatrics Unit, Lyon Institute for Elderly, Hospices civils de Lyon, Lyon, France; Research Clinic Centre (CRC)-VCF (Aging Brain Frailty), Lyon Institute For Elderly, Hospices civils de Lyon, Lyon, France.

Objectives: To estimate the attributable fraction of nursing home placement associated with cognitive impairment, neuropsychiatric symptoms, behavioral disorders, functional limitations, and caregiver burden.

Design: Longitudinal study conducted on the "MEMORA cohort" linked with both regional public health insurance and hospital discharge databases.

Setting: Memory center at the University Hospital of Lyon, France.

Participants: A sample of 2456 outpatients attending the memory center between 2012 and 2017.

Measures: Cognitive impairment, functional limitations, neuropsychiatric symptoms/behavioral disorders, and caregiver burden were measured with the Mini-Mental State Examination, the Instrumental Activities of Daily Living scale, the Neuropsychiatric Inventory (NPI), and a short version of the Zarit Burden Inventory, respectively. Sociodemographics characteristics were collected during the first visit. Comorbidities were gathered from the hospital discharge database. Dates of nursing home placement were obtained from the public health insurance database.

Results: More than 38% of nursing home placements were attributable to caregiver burden, and the attributable fraction associated with functional limitations exceeded 35%. Between 20% and 25% of nursing home placements were due to cognitive impairment whereas less than 16% were attributable to neuropsychiatric symptoms or behavioral disorders. The associations between anxiety or agitation and nursing home placement were mediated by caregiver burden. Apathy or aberrant motor behaviors were associated with a higher risk of nursing home placement independently of caregiver burden.

Conclusions/implications: Our findings suggest that a high proportion of nursing home placements are attributable to caregiver burden and functional limitations in outpatients attending a memory center. Cognitive impairment and neuropsychiatric symptoms or behavioral disorders contribute less to nursing home placements. Interventions directed to delay nursing home placement should emphasize actions toward reducing caregiver burden and functional limitations of patients.
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http://dx.doi.org/10.1016/j.jamda.2019.03.027DOI Listing
October 2019

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

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

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

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

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

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

Agonist and antagonist bind differently to 5-HT1A receptors during Alzheimer's disease: A post-mortem study with PET radiopharmaceuticals.

Neuropharmacology 2016 10 13;109:88-95. Epub 2016 May 13.

Lyon Neuroscience Research Center, Université Claude Bernard Lyon1, CNRS, INSERM, Lyon, France; Hospices Civils de Lyon, Lyon, France; CERMEP-Imaging Platform, Lyon, France. Electronic address:

PET imaging studies using 5-HT1A receptor radiotracers show a decreased density of this receptor in hippocampi of patients with Alzheimer's disease (AD) at advanced stages. However, current 5-HT1A receptor radiopharmaceuticals used in neuroimaging are antagonists, thought to bind to 5-HT1A receptors in different functional states (i.e., both the one which displays high affinity for agonists and is thought to mediate receptor activation, as well as the state which has low affinity for agonists). Comparing the PET imaging obtained using an agonist radiotracer, which binds selectively to functional receptors, with the PET imaging obtained using an antagonist radiotracer would therefore provide original information on 5-HT1A receptor impairment during AD. Quantitative autoradiography using [(18)F]F13640 and [(18)F]MPPF, a 5-HT1A agonist and antagonist, respectively, was measured in hippocampi of patients with AD (n = 25, at different Braak stages) and control subjects (n = 9). The neuronal density was measured in the same tissues by NeuN immunohistochemistry. The specific binding of both radiotracers was determined by addition of WAY-100635, a selective 5-HT1A receptor antagonist. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was in the pyramidal layer of CA1. Incubation with Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [(18)F]F13640 binding in hippocampal regions, confirming its preferential interaction with G-coupled receptors, and slightly increased [(18)F]MPPF binding. In the CA1 subfield, [(18)F]F13640 binding was significantly decreased at Braak stages I/II (-19%), Braak stages III/IV (-23%), and Braak stages V/VI (-36%) versus control. In contrast, [(18)F]MPPF binding was statistically reduced only at the most advanced Braak stages V/VI compared to control (-33%). Since [(18)F]F13640 and [(18)F]MPPF can be used in vivo in humans, this neuropharmacological paradigm supports testing the concept of functional imaging using agonist radiopharmaceuticals in future clinical studies.
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http://dx.doi.org/10.1016/j.neuropharm.2016.05.009DOI Listing
October 2016

Differential effects of amyloid-beta 1-40 and 1-42 fibrils on 5-HT1A serotonin receptors in rat brain.

Neurobiol Aging 2016 Apr 19;40:11-21. Epub 2015 Dec 19.

Université de Lyon; Lyon Neuroscience Research Center, CNRS UMR5292; INSERM U1028, Université Claude Bernard Lyon 1, Lyon, France; CERMEP-Imaging Platform, Lyon, France; Hospices Civils de Lyon, Lyon, France. Electronic address:

Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT(1A)R) after intrahippocampal injections of amyloid-beta 1-40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [(18)F]MPPF revealing an overexpression of 5-HT(1A)R in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT(1A)R reactivity by injecting them, separately, into the hippocampus or striatum of rats. [(18)F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT(1A)R in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils-induced 5-HT(1A)R expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.008DOI Listing
April 2016

Binding of the PET radiotracer [¹⁸F]BF227 does not reflect the presence of alpha-synuclein aggregates in transgenic mice.

Curr Alzheimer Res 2014 ;11(10):955-60

CERMEP-Imaging Platform, 59 boulevard Pinel, Lyon, F-69003, France.

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [(18)F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [(18)F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [(18)F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.
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http://dx.doi.org/10.2174/1567205011666141107154201DOI Listing
August 2015

Prenatal poly I:C age-dependently alters cannabinoid type 1 receptors in offspring: a longitudinal small animal PET study using [(18)F]MK-9470.

Exp Neurol 2014 Jul 10;257:162-9. Epub 2014 May 10.

Schizophrenia Research Institute, Sydney, Australia; ANSTO LifeSciences, ANSTO, PMB 1 Menai, NSW 2234, Australia; Neuroscience Research Australia, Randwick, NSW 2031, Australia; School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address:

Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [(18)F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32-42 (adolescence) and in the same animals again at PNDs 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies.
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http://dx.doi.org/10.1016/j.expneurol.2014.05.004DOI Listing
July 2014

Increases in [3H]muscimol and [3H]flumazenil binding in the dorsolateral prefrontal cortex in schizophrenia are linked to α4 and γ2S mRNA levels respectively.

PLoS One 2013 8;8(1):e52724. Epub 2013 Jan 8.

Schizophrenia Research Institute, Sydney, Australia.

Background: GABA(A) receptors (GABA(A)R) are composed of several subunits that determine sensitivity to drugs, synaptic localisation and function. Recent studies suggest that agonists targeting selective GABA(A)R subunits may have therapeutic value against the cognitive impairments observed in schizophrenia. In this study, we determined whether GABA(A)R binding deficits exist in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia and tested if changes in GABA(A)R binding are related to the changes in subunit mRNAs. The GABA orthosteric and the benzodiazepine allosteric binding sites were assessed autoradiographically using [(3)H]Muscimol and [(3)H]Flumazenil, respectively, in a large cohort of individuals with schizophrenia (n = 37) and their matched controls (n = 37). We measured, using qPCR, mRNA of β (β1, β2, β3), γ (γ1, γ2, γ2S for short and γ2L for long isoform, γ3) and δ subunits and used our previous measurements of GABA(A)R α subunit mRNAs in order to relate mRNAs and binding through correlation and regression analysis.

Results: Significant increases in both [(3)H]Muscimol (p = 0.016) and [(3)H]Flumazenil (p = 0.012) binding were found in the DLPFC of schizophrenia patients. Expression levels of mRNA subunits measured did not show any significant difference in schizophrenia compared to controls. Regression analysis revealed that in schizophrenia, the [(3)H]Muscimol binding variance was most related to α4 mRNA levels and the [(3)H]Flumazenil binding variance was most related to γ2S subunit mRNA levels. [(3)H]Muscimol and [(3)H]Flumazenil binding were not affected by the lifetime anti-psychotics dose (chlorpromazine equivalent).

Conclusions: We report parallel increases in orthosteric and allosteric GABA(A)R binding sites in the DLPFC in schizophrenia that may be related to a "shift" in subunit composition towards α4 and γ2S respectively, which may compromise normal GABAergic modulation and function. Our results may have implications for the development of treatment strategies that target specific GABA(A)R receptor subunits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052724PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540049PMC
August 2013

Differential treatment regimen-related effects of HU210 on CB(1) and D(2)-like receptor functionality in the rat basal ganglia.

Pharmacology 2012 1;89(1-2):64-73. Epub 2012 Feb 1.

LifeSciences Division, Australian Nuclear Science and Technology Organisation, Lucas Heights, N.S.W., Australia.

Background/aims: Functional linkages between the cannabinoid CB(1) and the dopaminergic systems have been reported although the observations and the mechanisms hypothesizing their interactions at the G protein-coupled receptor (GPCR) functionality level are conflicting.

Methods: Administration of a potent cannabinoid agonist, HU210, at various doses (25-100 μg/kg) and treatment regimens (1- to 14-day treatment) in rats was carried out to investigate the effect of HU210 treatment on the CB(1) and D(2)-like agonist-mediated GPCR activation.

Results: The desensitizations (reduced coupling) of both D(2) agonist- and CB(1) agonist-mediated GPCR activation was found to be treatment duration dependent and region specific, suggesting implication of receptor tolerance and adaptation due to the cannabinoid treatment. The effect of HU210 on the CB(1) agonist-mediated GPCR desensitization in all treatment groups was not dose dependent.

Conclusions: The desensitization of D(2)-like receptors found after a cannabinoid treatment in this study strengthens the evidence that the two neurotransmitter systems interact at the intercellular level; this interaction might occur via multiple mechanisms, which also vary according to region.
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http://dx.doi.org/10.1159/000335368DOI Listing
July 2012

Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the "Two Hit" Hypothesis for the Development of Schizophrenia.

ISRN Psychiatry 2012 7;2012:451865. Epub 2012 Jun 7.

Schizophrenia Research Institute, Sydney, NSW 2010, Australia ; Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.

Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [(3)H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15-18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia.
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http://dx.doi.org/10.5402/2012/451865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658855PMC
June 2013

Comparison of Cannabinoid CB(1) Receptor Binding in Adolescent and Adult Rats: A Positron Emission Tomography Study Using [F]MK-9470.

Int J Mol Imaging 2011 11;2011:548123. Epub 2011 Dec 11.

Schizophrenia Research Institute, Sydney, Australia.

Despite the important role of cannabinoid CB(1) receptors (CB(1)R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB(1)R in adolescent and adult rats in vivo using positron emission tomography with [(18)F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [(18)F]MK-9470 values between the two groups revealed a main effect of age (F(1,109)=5.0, P = 0.02) on [(18)F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [(3)H]CP55,940 (F(10,99)=140.1, P < 0.0001). This ontogenetic pattern, suggesting increase of CB(1)R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period.
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http://dx.doi.org/10.1155/2011/548123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236487PMC
August 2012

Increased brain metabolism after acute administration of the synthetic cannabinoid HU210: a small animal PET imaging study with 18F-FDG.

Brain Res Bull 2012 Feb 1;87(2-3):172-9. Epub 2011 Dec 1.

ANSTO LifeSciences, Australian Nuclear Science and Technology Organisation, Lucas Heights, NSW 2234, Australia.

Cannabis use has been shown to alter brain metabolism in both rat models and humans although the observations between both species are conflicting. In the present study, we examined the short term effects of a single-dose injection of the synthetic cannabinoid agonist HU210 on glucose metabolism in the rat brain using small animal (18)F-2-fluoro-deoxyglucose (FDG) Positron Emission Tomography (PET) 15 min (Day 1) and 24h (Day 2) post-injection of the agonist in the same animal. Young adult male Wistar rats received an intra-peritoneal injection of HU210 (100 μg/kg, n=7) or vehicle (n=5) on Day 1. Approximately 1mCi of (18)F-FDG was injected intravenously into each animal at 15 min (Day 1) and 24h (Day 2) post-injection of HU210. A 5-min Computer Tomography (CT) scan followed by a 20-min PET scan was performed 40 min after each (18)F-FDG injection. Standardised Uptake Values (SUVs) were calculated for 10 brain regions of interest (ROIs). Global increased SUVs in the whole brain, hence global brain metabolism, were observed following HU210 treatment on Day 1 compared to the controls (21%, P<0.0001), but not in individual brain regions. On Day 2, however, no statistically significant differences were observed between the treated and control groups. At the 24h time point (Day 2), SUVs in the HU210 treated group returned to control levels (21-30% decrease compared to Day 1), in all ROIs investigated (P<0.0001). In the control group, SUVs did not differ between the two acquisition days in all brain regions. The present results suggest that high-dose HU210 increases brain glucose metabolism in the rat brain shortly after administration, in line with normalised human in vivo studies, an effect that was no longer apparent 24 h later.
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http://dx.doi.org/10.1016/j.brainresbull.2011.11.011DOI Listing
February 2012

GABA(A) receptor density is altered by cannabinoid treatment in the hippocampus of adult but not adolescent rats.

Brain Res 2010 Sep 17;1351:238-245. Epub 2010 Jun 17.

Schizophrenia Research Institute, Sydney, Australia; ANSTO Life Sciences, Sydney, Australia. Electronic address:

Cannabinoids are known to induce transient psychotic symptoms and cognitive dysfunction in healthy individuals and contribute to trigger schizophrenia in vulnerable individuals, particularly during adolescence. Converging preclinical evidence suggests important interactions between cannabinoid and GABAergic systems. In the present study, we compared the effects of cannabinoid treatment on GABA(A) receptor binding in the brain of adolescent and adult rats. Adolescent (5 weeks old) and adult (10 weeks old) rats were treated with the synthetic cannabinoid HU210 (25, 50 or 100 microg/kg/day) or vehicle for 1, 4 or 14 days. Rats were sacrificed 24 h after the last injection and GABA(A) receptor density was measured in several brain regions using [(35)S]TBPS and in vitro autoradiography. Adolescent rats had higher numbers of GABA(A) receptors compared to adults. A 24% increase of binding in adult rats treated with 100 microg/kg HU210 for 14 days compared to controls was observed in the CA1 region of the hippocampus (16.1 versus 12.9 fmol/mg tissue equivalent, t=2.720, p<0.05). HU210 did not affect GABA(A) receptors in adolescent rats in any treatment regimen and in adult rats treated with HU210 for 1 or 4 days. These data suggest that long-term, high-dose treatment with HU210 increases GABA(A) receptors in the hippocampus of adult rats, changes that may interfere with associated hippocampal cognitive functions such as learning and memory. In addition, our results suggest that the adolescent brain does not display the same compensatory mechanisms that are activated in the adult brain following cannabinoid treatment.
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http://dx.doi.org/10.1016/j.brainres.2010.06.032DOI Listing
September 2010

Looking for a 5-HT7 radiotracer for positron emission tomography.

Bioorg Med Chem Lett 2010 Jun 24;20(12):3730-3. Epub 2010 Apr 24.

Université de Lyon, Université Lyon 1, CNRS, ICBMS (UMR CNRS 5246), Lyon, France.

In search of a serotonin 5-HT(7) radiotracer for positron emission tomography, we developed 1-[2-[(2S)-1-(phenylsulfonyl)pyrrolidin-2-yl]ethyl]piperidin-4-yl 4-fluorobenzoate. After labeling in good yield with fluorine-18 via nitro for fluorine exchange, preliminary biological experiments with autoradiographies failed to evidence any specific 5-HT(7) receptor delineation.
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http://dx.doi.org/10.1016/j.bmcl.2010.04.076DOI Listing
June 2010

[18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging.

Eur J Nucl Med Mol Imaging 2010 Mar 30;37(3):594-605. Epub 2009 Sep 30.

Laboratory of Neuropharmacology, Université de Lyon, EAC CNRS 5006, Lyon, France.

Purpose: The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors. Since all clinical PET 5-HT(1A) radiopharmaceuticals are antagonists, it is of great interest to develop a( 18)F labelled agonist.

Methods: F15599 (3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone) is a novel ligand with high affinity and selectivity for 5-HT(1A) receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT(1A) receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [(18)F]MPPF, a validated 5-HT(1A) antagonist radiopharmaceutical.

Results: The chemical and radiochemical purities of [(18)F]F15599 were >98%. In vitro [(18)F]F15599 binding was consistent with the known 5-HT(1A) receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [(18)F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [(18)F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT(1A) antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [(18)F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT(1A) receptors.

Conclusion: [(18)F]F15599 is a radiofluorinated agonist presenting interesting characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT(1A) receptors. Its differential labelling of 5-HT(1A) receptors in vitro and in vivo may result from its reported preferential interaction with receptors coupled to specific G-protein subtypes.
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http://dx.doi.org/10.1007/s00259-009-1274-yDOI Listing
March 2010

Effects of amyloid-β peptides on the serotoninergic 5-HT1A receptors in the rat hippocampus.

Neurobiol Aging 2011 Jan 26;32(1):103-14. Epub 2009 Feb 26.

Laboratory of Neuropharmacology, FRE CNRS 3006, Univ Lyon 1, Université de Lyon, France.

A recent [(18)F]MPPF-positron emission tomography study has highlighted an overexpression of 5-HT(1A) receptors in the hippocampus of patients with mild cognitive impairment compared to a decrease in those with Alzheimer's disease (AD) [Truchot, L., Costes, S.N., Zimmer, L., Laurent, B., Le Bars, D., Thomas-Antérion, C., Croisile, B., Mercier, B., Hermier, M., Vighetto, A., Krolak-Salmon, P., 2007. Up-regulation of hippocampal serotonin metabolism in mild cognitive impairment. Neurology 69 (10), 1012-1017]. We used in vivo and in vitro neuroimaging to evaluate the longitudinal effects of injecting amyloid-β (Aβ) peptides (1-40) into the dorsal hippocampus of rats. In vivo microPET imaging showed no significant change in [(18)F]MPPF binding in the dorsal hippocampus over time, perhaps due to spatial resolution. However, in vitro autoradiography with [(18)F]MPPF (which is antagonist) displayed a transient increase in 5-HT(1A) receptor density 7 days after Aβ injection, whereas [(18)F]F15599 (a radiolabelled 5-HT(1A) agonist) binding was unchanged suggesting that the overexpressed 5-HT(1A) receptors were in a non-functional state. Complementary histology revealed a loss of glutamatergic neurons and an intense astroglial reaction at the injection site. Although a neurogenesis process cannot be excluded, we propose that Aβ injection leads to a transient astroglial overexpression of 5-HT(1A) receptors in compensation for the local neuronal loss. Exploration of the functional consequences of these serotoninergic modifications during the neurodegenerative process may have an impact on therapeutics targeting 5-HT(1A) receptors in AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2009.01.008DOI Listing
January 2011

Automated radiosynthesis of the Pittsburg compound-B using a commercial synthesizer.

Nucl Med Commun 2008 Oct;29(10):920-6

CERMEP-Imagerie du Vivant, PET Department, Université Lyon 1, Lyon, France.

Background: The Pittsburgh compound-B ([11C]PIB) is a highly interesting radiotracer for imaging amyloid plaques in Alzheimer's disease by positron emission tomography (PET). An increasing number of PET centres schedule its transfer for clinical studies and therefore are interested in its automated synthesis.

Method: With the aim of flexibility, we reported the first fully automated synthesis of [11C]PIB with the coupling of two commercial synthesizers.

Results: [11C]PIB was prepared from 2-(4'-aminophenyl)-6-hydroxybenzothiazole by [11C]methyl triflate methylation reacting in an high-performance liquid chromatography loop and resulting in a total radiochemical yield of 13+/-15% after a synthesis time of 25 min. The specific activity of [11C]PIB was 20-60 GBq/micromol and its radiochemical purity is more than 99%.

Conclusion: The rapid synthesis and the automatic auto-cleaning procedure allow convenient and reproducible [11C]PIB synthesis to be performed during the same day for preclinical or clinical PET scans.
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http://dx.doi.org/10.1097/MNM.0b013e328304e0e1DOI Listing
October 2008

The potential of a radiosensitive intracerebral probe to monitor 18F-MPPF binding in mouse hippocampus in vivo.

J Nucl Med 2008 Jul 13;49(7):1155-61. Epub 2008 Jun 13.

IMNC, UMR8165 CNRS-Université of Paris 7 and Paris 11, Orsay, France.

Unlabelled: As mouse imaging has become more challenging in preclinical research, efforts have been made to develop dedicated PET systems. Although these systems are currently used for the study of physiopathologic murine models, they present some drawbacks for brain studies, including a low temporal resolution that limits the pharmacokinetic study of radiotracers. The aim of this study was to demonstrate the ability of a radiosensitive intracerebral probe to measure the binding of a radiotracer in the mouse brain in vivo.

Methods: The potential of a probe 0.25 mm in diameter for pharmacokinetic studies was assessed. First, Monte Carlo simulations followed by experimental studies were used to evaluate the detection volume and sensitivity of the probe and its adequacy for the size of loci in the mouse brain. Second, ex vivo autoradiography of 5-hydroxytryptamine receptor 1A (5-HT(1A)) receptors in the mouse brain was performed with the PET radiotracer 2'-methoxyphenyl-(N-2'-pyridinyl)-p-(18)F-fluorobenzamidoethylpiperazine ((18)F-MPPF). Finally, the binding kinetics of (18)F-MPPF were measured in vivo in both the hippocampus and the cerebellum of mice.

Results: Both the simulations and the experimental studies demonstrated the feasibility of using small probes to measure radioactive concentrations in specific regions of the mouse brain. Ex vivo autoradiography showed a heterogeneous distribution of (18)F-MPPF consistent with the known distribution of 5-HT(1A) in the mouse brain. Finally, the time-activity curves obtained in vivo were reproducible and validated the capacity of the new probe to accurately measure (18)F-MPPF kinetics in the mouse hippocampus.

Conclusion: Our results demonstrate the ability of the tested radiosensitive intracerebral probe to monitor binding of PET radiotracers in anesthetized mice in vivo, with high temporal resolution suited for compartmental modeling.
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http://dx.doi.org/10.2967/jnumed.107.050047DOI Listing
July 2008

Synthesis and biological evaluation in rat and cat of [18F]12ST05 as a potential 5-HT6 PET radioligand.

Nucl Med Biol 2007 Nov 21;34(8):995-1002. Epub 2007 Sep 21.

Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, UMR CNRS 5246, Université Lyon 1, Université de Lyon, Lyon, 69677 (Cermep), France.

Introduction: 5-hydroxytryptamine (5-HT)6 receptors represent one of the more recently discovered serotoninergic receptor family. However, no 5-HT6 positron emission tomography (PET) radiotracer is currently used in clinical imaging studies. The purpose of this study was to propose the first fluorinated PET radiotracer for this brain receptor.

Methods: A new compound presenting in vitro high affinity towards the serotoninergic 5-HT6 receptor, N-[2-(1-[(4-fluorophenyl)sulfonyl]-1H-indol-4-yloxy)ethyl]-N,N-dimethylamine, was labelled with fluorine 18 via a nitro-/fluoronucleophilic substitution. Biological evaluations included (i) in vitro and ex vivo autoradiographies in rat brain and (ii) a PET scan on anaesthetized cat.

Results And Conclusion: Although the radioligand showed excellent brain penetration, it did not reveal any specific binding to the 5-HT6 receptors indicating that this radiotracer is not suitable for mapping 5-HT6 receptors using PET.
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http://dx.doi.org/10.1016/j.nucmedbio.2007.07.002DOI Listing
November 2007