Denis Guilloteau - Academia.edu (original) (raw)
Papers by Denis Guilloteau
![Research paper thumbnail of Synthesis, radiolabeling, and preliminary biological evaluation of [3H]-1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine, a potent antagonist radioligand for the P2X7 receptor](https://attachments.academia-assets.com/101039408/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry Letters, 2004
Medicinal chemistry Medicinal chemistry V 1100 Synthesis, Radiolabeling and Preliminary Biologica... more Medicinal chemistry Medicinal chemistry V 1100 Synthesis, Radiolabeling and Preliminary Biological Evaluation of Radiolabeled 5-Methyl-6-nitroquipazine, a Potential Radioligand for the Serotonin Transporter.-The title compound is synthesized as an analogue of the potent and selective serotonin transporter inhibitor 6-nitroquipazine and radiolabeled with tritium and the positron emitter 11 C. A low non-specific binding to the serotonin transporter protein (5-HTT) is observed with tritium-labeled compound (I), making this ligand a promising radioligand for in vitro studies of 5-HTT. The high binding constant, specific in vivo binding and the facile labeling makes 11 C-labeled compound (II) a promising candidate for visualization of the serotonin transporter with positron emission tomography.
Journal of Lipid Research, 1997
The influence of aging (2,6,12, and 24 months) on hippocampal lipid composition and neurochemical... more The influence of aging (2,6,12, and 24 months) on hippocampal lipid composition and neurochemical markers (endogenous noradrenaline, serotonin levels, monoamine oxidase (MOA) activities) was studied in rats fed a control or an n-3 polyunsaturated fatty acid (PUFA)-deficient diet. The n-3 PUFA deficiency reduced the 22:6(n-3) level, compensated by the increase in 22:5(n-6). However, the difference in 22:6(n-3) content between control and deficient rats was less between 2 and 12 months and then became stable. There was an overall age-induced decrease in the major phospholipid classes phosphatidylethanolamine (PE) and phosphatidylcholine (PC) whereas the minor classes, phosphatidylinosi-to1 (PI), phosphatidylserine (PS), and sphingomyelin (SM), were greatly increased, regardless of diet. The n-3 PUFA deficiency induced a reduction in the PS level, concomitant with a higher level in MAO-B activity as compared to control rats at the age of 24 months. The age-related evolution of the MAO-B activity was parallel with that of noradrenaline levels in both dietary groups. The noradrenaline and serotonin levels were modified according to age but without effect of the n-3 PUFA deficiency.l Results showed that the hippocampus sustained specific age-induced modifications in lipid composition and neurotransmission factors, often with a transition period hetween 6 and 12 months.-Delion, S., S. Chalon, D. GuiUoteau, B. Lejeune, J-C. Besnard, and G. Durand. Age-related changes in phospholipid fatty acid composition and monoaminergic neurotransmission in the hippocampus of rats fed a balanced or an n-3 polyunsaturated fatty aciddeficient diel.
Journal of Lipid Research, 2000
We studied the effects of a diet chronically deficient in ␣-linolenic acid, the precursor of long... more We studied the effects of a diet chronically deficient in ␣-linolenic acid, the precursor of long-chain n-3 polyunsaturated fatty acids, on dopaminergic neurotransmission in the shell region of the nucleus accumbens of rats. In vivo microdialysis experiments showed increased basal levels of dopamine and decreased basal levels of metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in awake rats from the deficient group compared to controls. The release of dopamine under KCl stimulation was similar in both dietary groups. By contrast, the release of dopamine from the vesicular storage pool under tyramine stimulation was 90% lower in the deficient than in the control rats. Autoradiographic studies in the same cerebral region revealed a 60% reduction in the vesicular monoamine transporter sites in the deficient group. Dopamine D 2 receptors were 35% increased in these rats compared to controls, whereas no change occurred for D 1 receptors and membrane dopamine transporters. These results demonstrated that chronic n-3 polyunsaturated fatty acid deficiency modifies several factors of dopaminergic neurotransmission in the nucleus accumbens. These findings are in agreement with the changes in dopaminergic neurotransmission already observed in the frontal cortex, and with the behavioral disturbances described in these deficient rats.
Journal of Lipid Research, 2002
Previous investigations have shown that the lipid composition of cerebral membranes and dopaminer... more Previous investigations have shown that the lipid composition of cerebral membranes and dopaminergic neurotransmission are changed under chronic α-linolenic acid diet deficiency in the rat. This study investigated whether these changes could be reversed and if the stage of brain maturation might play a role in the recovery process. The effects of reversion on the fatty acid (FA) composition and dopaminergic neurotransmission were studied in brain regions known to be affected by such deficiency (i.e., the prefrontal cortex and nucleus accumbens) in 2-month-old animals. Dopamine release under pharmacological stimulation was studied using a dual-probe microdialysis method. Vesicular monoamine transporters were studied using quantitative autoradiography. The reversal diet, with adequate levels of n-6 and n-3 polyunsaturated fatty acids (PUFAs), was given to deficient rats at different stages of development (0, 7, 14, or 21 days of age). The results showed that when given during the lact...
Clinical Chemistry, 1990
Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularl... more Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularly occult familial MTC. In previous radioimmunoassays of calcitonin, polyclonal antibodies were used. Here we evaluate a new two-site immunoradiometric assay (IRMA) of calcitonin based on use of monoclonal antibodies. We assayed samples from healthy subjects, patients with renal failure, and subjects from families affected by MTC. Basal values for healthy subjects were all less than 10 ng/L. Renal failure is associated with increased basal CT. The CT peak under pentagastrin stimulation in healthy patients was less than 30 ng/L. In familial screening, basal values greater than 10 ng/L or peak values greater than 30 ng/L correspond to subjects with histologically confirmed MCT or micro-MCT. Polyclonal RIA performed in the same subjects failed to detect the moderate increase of CT that IRMA demonstrated. Preliminary results indicate that this new method may allow earlier detection of CT incr...
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1988
The uptake and release of mIBG, a tracer of the monoamine uptake and storage function, were studi... more The uptake and release of mIBG, a tracer of the monoamine uptake and storage function, were studied on superfused rat cerebral cortex sections. mIBG was taken up and released by a mechanism comparable to that of norepinephrine (NE), but this storage appeared to be less specific for mIBG than for NE. This implies that when mIBG is used as a scintigraphic tracer of monoaminergic synaptic vesicles, imaging should be delayed long enough to ensure release of the molecule from its nonspecific binding sites,
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1991
The accumulation of [3H]spiperone and [3H]dopamine was measured in striatum and pituitary gland s... more The accumulation of [3H]spiperone and [3H]dopamine was measured in striatum and pituitary gland slices of rat. Contrary to [3H]dopamine, [3H]spiperone storage was similar in striatum and pituitary gland. In addition, [3H]spiperone accumulation was not diminished by reserpine and tetrabenazine. These data show that spiperone is not subject to the granular uptake/storage mechanism and suggest that spiperone and its derivatives are specific ligands for dopamine receptors only.
The Journal of Nutrition, 1998
We studied the effects of a fish oil enriched diet on fatty acid composition of cerebral membrane... more We studied the effects of a fish oil enriched diet on fatty acid composition of cerebral membranes and on several neurochemical and behavioral variables of monoaminergic function in rats. The frontal cortex, striatum, hippocampus and cerebellum were studied in rats fed fish oil (FPO, 50% salmon oil ϩ 50% palm oil), which provided an (n-6)/(n-3) polyunsaturated fatty acid (PUFA) ratio of 0.14 versus 6.19 in controls fed a diet containing a mixture of African peanut oil and rapeseed oil. In the FPO group compared to the control group, the major modifications in fatty acid composition of cerebral membranes included the following: higher levels in 22:6(n-3), lower levels in 20:4(n-6) and a significantly greater proportion of phosphatidylserine. Dopamine levels were 40% greater in the frontal cortex of rats fed FPO than from those fed the control diet. In this cerebral region there was also a reduction in monoamine oxidase B (MAO-B) activity and greater binding to dopamine D 2 receptors. By contrast, a lower binding to dopamine D 2 receptors (Ϫ7%) was observed in the striatum. Ambulatory activity was also reduced in FPO-fed rats, possibly related to observed changes in striatal dopaminergic receptors. This suggested that the level of (n-6) PUFA, which was considerably lower in the FPO diet than in the control diet, could act on locomotion through an effect on striatal dopaminergic function, whereas the high level of (n-3) PUFA could act on cortical dopaminergic function.
The Journal of Neuroscience, 2001
Contrast media & molecular imaging, 2018
In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging h... more In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, inc...
![Research paper thumbnail of Translocator Protein (18 kDa) Mapping with [(125)I]-CLINDE in the Quinolinic Acid Rat Model of Excitotoxicity: A Longitudinal Comparison with Microglial Activation, Astrogliosis, and Neuronal Death](https://attachments.academia-assets.com/95708295/thumbnails/1.jpg)
](Molecular imaging
Excitotoxicity leads to an inflammatory reaction involving an overexpression of: translocator pro... more Excitotoxicity leads to an inflammatory reaction involving an overexpression of: translocator protein 18 kDa (TSPO) in cerebral microglia and astrocytes. Therefore, we performed ex vivo explorations with [(125)]-CLINDE, a TSPO-specific radioligand, to follow the time course of TSPO expression, in parallel with lesion progression, over 90 days after induction of cerebral excitotoxicity in rats intrastriatally injected with quinolinic acid. Biodistribution data showed a significant increase in CLINDE uptake on the injured side from 1 days postlesion (dpl); the maximal striatal binding values evidenced a plateau between 7 and 30 dpl. [(125)I]-CLINDE binding was displaced from the lesion by PK11195, suggesting TSPO specificity. These results were confirmed by ex vivo autoradiography. Combined immunohistochemical studies showed a marked increase in microglial expression in the lesion, peaking at 14 dpl, and astrocytic reactivity enhanced at 7 and 14 dpl, whereas a prominent neuronal cell...
International Journal of Nuclear Medicine and Biology, 1986
This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. ... more This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. Biodistribution demonstrated an early and preferential uptake by both adrenal glands and heart and then storage in the adrenal gland of both agents, however I-CPP is less stable in vivo than mIBG. Reserpine depletion study in rat indicated that the I-CPP and mIBG uptake mechanisms are not similar.
International Journal of Molecular Sciences, 2017
Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wi... more Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals' binding affinity, or similar expression in activated microglia regardless of its polarization (pro-or anti-inflammatory state), and these limitations narrow its potential interest. We overview alternative molecular targets, for which dedicated radiopharmaceuticals have been proposed, including receptors (purinergic receptors P2X7, cannabinoid receptors, α7 and α4β2 nicotinic acetylcholine receptors, adenosine 2A receptor, folate receptor β) and enzymes (cyclooxygenase, nitric oxide synthase, matrix metalloproteinase, β-glucuronidase, and enzymes of the kynurenine pathway), with a particular focus on their respective contribution for the understanding of microglial involvement in neurodegenerative diseases. We discuss opportunities for these potential molecular targets for PET imaging regarding their selectivity for microglia expression and polarization, in relation to the mechanisms by which microglia actively participate in both toxic and neuroprotective actions in brain diseases, and then take into account current clinicians' expectations.
La Revue de Médecine Interne, 2011
Contrast Media & Molecular Imaging, 2017
Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gath... more Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatoryfociare crucial for an adequate care for patients. In brain diseases,in vivopositron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the...
International Journal of Molecular Sciences, 2017
In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positro... more In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease's stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia's role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.
Frontiers in Medicine, 2017
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 28, 2016
Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the ex... more Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the existing literature is confounded by heterogeneous approaches to studying SCD. We assessed the differential cognitive, affective, and neuroimaging correlates of two aspects of SCD: reporting high cognitive difficulties on a self-rated questionnaire versus consulting at a memory clinic. We compared 28 patients from a memory clinic with isolated SCD, 35 community-recruited elders with similarly high levels of self-reported cognitive difficulties, and 35 community-recruited controls with low self-reported cognitive difficulties. Increased anxiety and β-amyloid deposition were observed in both groups with high self-reported difficulties, whereas subclinical depression and (hippocampal) atrophy were specifically associated with medical help seeking. Cognitive tests showed no group differences. These results further validate the concept of SCD in both community- and clinic-based groups. Yet, rec...
Journal of Pharmacology and Experimental Therapeutics, Jul 1, 1997
N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)nortropane (β-CDIT), a new iodi... more N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)nortropane (β-CDIT), a new iodinated tropane derivative, has been synthesized and radiolabeled with iodine. [ 125 I]β-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [ 125 I]β-CDIT bound to a single high-affinity site. The K d value was 0.18 ± 0.07 nM, and the corresponding B max value was 500 ± 80 fmol/mg of protein. The pharmacological profile of specific [ 125 I]β-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [ 3 H]paroxetine and [ 3 H]nisoxetine showed a very low affinity of β-CDIT for the 5-hydroxytryptamine ( K i = 50 nM) and norepinephrine ( K i = 500 nM) transporters compared with β-CIT (corresponding K i values were 3 and 80 nM). In contrast, the competition of β-CDIT with [ 3 H]GBR 12935 in the striatal region ( K i = 29 nM) was of the same order of value as for β-CIT ( K i = 27.5 nM). Behavioral experiments in mice showed that both β-CDIT and β-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [ 125 I]β-CDIT demonstrated high densities of [ 125 I]β-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [ 125 I]β-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
Nuclear Medicine and Biology, 2008
Bioorganic & Medicinal Chemistry Letters, 2004
Medicinal chemistry Medicinal chemistry V 1100 Synthesis, Radiolabeling and Preliminary Biologica... more Medicinal chemistry Medicinal chemistry V 1100 Synthesis, Radiolabeling and Preliminary Biological Evaluation of Radiolabeled 5-Methyl-6-nitroquipazine, a Potential Radioligand for the Serotonin Transporter.-The title compound is synthesized as an analogue of the potent and selective serotonin transporter inhibitor 6-nitroquipazine and radiolabeled with tritium and the positron emitter 11 C. A low non-specific binding to the serotonin transporter protein (5-HTT) is observed with tritium-labeled compound (I), making this ligand a promising radioligand for in vitro studies of 5-HTT. The high binding constant, specific in vivo binding and the facile labeling makes 11 C-labeled compound (II) a promising candidate for visualization of the serotonin transporter with positron emission tomography.
Journal of Lipid Research, 1997
The influence of aging (2,6,12, and 24 months) on hippocampal lipid composition and neurochemical... more The influence of aging (2,6,12, and 24 months) on hippocampal lipid composition and neurochemical markers (endogenous noradrenaline, serotonin levels, monoamine oxidase (MOA) activities) was studied in rats fed a control or an n-3 polyunsaturated fatty acid (PUFA)-deficient diet. The n-3 PUFA deficiency reduced the 22:6(n-3) level, compensated by the increase in 22:5(n-6). However, the difference in 22:6(n-3) content between control and deficient rats was less between 2 and 12 months and then became stable. There was an overall age-induced decrease in the major phospholipid classes phosphatidylethanolamine (PE) and phosphatidylcholine (PC) whereas the minor classes, phosphatidylinosi-to1 (PI), phosphatidylserine (PS), and sphingomyelin (SM), were greatly increased, regardless of diet. The n-3 PUFA deficiency induced a reduction in the PS level, concomitant with a higher level in MAO-B activity as compared to control rats at the age of 24 months. The age-related evolution of the MAO-B activity was parallel with that of noradrenaline levels in both dietary groups. The noradrenaline and serotonin levels were modified according to age but without effect of the n-3 PUFA deficiency.l Results showed that the hippocampus sustained specific age-induced modifications in lipid composition and neurotransmission factors, often with a transition period hetween 6 and 12 months.-Delion, S., S. Chalon, D. GuiUoteau, B. Lejeune, J-C. Besnard, and G. Durand. Age-related changes in phospholipid fatty acid composition and monoaminergic neurotransmission in the hippocampus of rats fed a balanced or an n-3 polyunsaturated fatty aciddeficient diel.
Journal of Lipid Research, 2000
We studied the effects of a diet chronically deficient in ␣-linolenic acid, the precursor of long... more We studied the effects of a diet chronically deficient in ␣-linolenic acid, the precursor of long-chain n-3 polyunsaturated fatty acids, on dopaminergic neurotransmission in the shell region of the nucleus accumbens of rats. In vivo microdialysis experiments showed increased basal levels of dopamine and decreased basal levels of metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in awake rats from the deficient group compared to controls. The release of dopamine under KCl stimulation was similar in both dietary groups. By contrast, the release of dopamine from the vesicular storage pool under tyramine stimulation was 90% lower in the deficient than in the control rats. Autoradiographic studies in the same cerebral region revealed a 60% reduction in the vesicular monoamine transporter sites in the deficient group. Dopamine D 2 receptors were 35% increased in these rats compared to controls, whereas no change occurred for D 1 receptors and membrane dopamine transporters. These results demonstrated that chronic n-3 polyunsaturated fatty acid deficiency modifies several factors of dopaminergic neurotransmission in the nucleus accumbens. These findings are in agreement with the changes in dopaminergic neurotransmission already observed in the frontal cortex, and with the behavioral disturbances described in these deficient rats.
Journal of Lipid Research, 2002
Previous investigations have shown that the lipid composition of cerebral membranes and dopaminer... more Previous investigations have shown that the lipid composition of cerebral membranes and dopaminergic neurotransmission are changed under chronic α-linolenic acid diet deficiency in the rat. This study investigated whether these changes could be reversed and if the stage of brain maturation might play a role in the recovery process. The effects of reversion on the fatty acid (FA) composition and dopaminergic neurotransmission were studied in brain regions known to be affected by such deficiency (i.e., the prefrontal cortex and nucleus accumbens) in 2-month-old animals. Dopamine release under pharmacological stimulation was studied using a dual-probe microdialysis method. Vesicular monoamine transporters were studied using quantitative autoradiography. The reversal diet, with adequate levels of n-6 and n-3 polyunsaturated fatty acids (PUFAs), was given to deficient rats at different stages of development (0, 7, 14, or 21 days of age). The results showed that when given during the lact...
Clinical Chemistry, 1990
Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularl... more Calcitonin (CT) assay is essential for recognizing medullary thyroid carcinoma (MTC), particularly occult familial MTC. In previous radioimmunoassays of calcitonin, polyclonal antibodies were used. Here we evaluate a new two-site immunoradiometric assay (IRMA) of calcitonin based on use of monoclonal antibodies. We assayed samples from healthy subjects, patients with renal failure, and subjects from families affected by MTC. Basal values for healthy subjects were all less than 10 ng/L. Renal failure is associated with increased basal CT. The CT peak under pentagastrin stimulation in healthy patients was less than 30 ng/L. In familial screening, basal values greater than 10 ng/L or peak values greater than 30 ng/L correspond to subjects with histologically confirmed MCT or micro-MCT. Polyclonal RIA performed in the same subjects failed to detect the moderate increase of CT that IRMA demonstrated. Preliminary results indicate that this new method may allow earlier detection of CT incr...
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1988
The uptake and release of mIBG, a tracer of the monoamine uptake and storage function, were studi... more The uptake and release of mIBG, a tracer of the monoamine uptake and storage function, were studied on superfused rat cerebral cortex sections. mIBG was taken up and released by a mechanism comparable to that of norepinephrine (NE), but this storage appeared to be less specific for mIBG than for NE. This implies that when mIBG is used as a scintigraphic tracer of monoaminergic synaptic vesicles, imaging should be delayed long enough to ensure release of the molecule from its nonspecific binding sites,
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1991
The accumulation of [3H]spiperone and [3H]dopamine was measured in striatum and pituitary gland s... more The accumulation of [3H]spiperone and [3H]dopamine was measured in striatum and pituitary gland slices of rat. Contrary to [3H]dopamine, [3H]spiperone storage was similar in striatum and pituitary gland. In addition, [3H]spiperone accumulation was not diminished by reserpine and tetrabenazine. These data show that spiperone is not subject to the granular uptake/storage mechanism and suggest that spiperone and its derivatives are specific ligands for dopamine receptors only.
The Journal of Nutrition, 1998
We studied the effects of a fish oil enriched diet on fatty acid composition of cerebral membrane... more We studied the effects of a fish oil enriched diet on fatty acid composition of cerebral membranes and on several neurochemical and behavioral variables of monoaminergic function in rats. The frontal cortex, striatum, hippocampus and cerebellum were studied in rats fed fish oil (FPO, 50% salmon oil ϩ 50% palm oil), which provided an (n-6)/(n-3) polyunsaturated fatty acid (PUFA) ratio of 0.14 versus 6.19 in controls fed a diet containing a mixture of African peanut oil and rapeseed oil. In the FPO group compared to the control group, the major modifications in fatty acid composition of cerebral membranes included the following: higher levels in 22:6(n-3), lower levels in 20:4(n-6) and a significantly greater proportion of phosphatidylserine. Dopamine levels were 40% greater in the frontal cortex of rats fed FPO than from those fed the control diet. In this cerebral region there was also a reduction in monoamine oxidase B (MAO-B) activity and greater binding to dopamine D 2 receptors. By contrast, a lower binding to dopamine D 2 receptors (Ϫ7%) was observed in the striatum. Ambulatory activity was also reduced in FPO-fed rats, possibly related to observed changes in striatal dopaminergic receptors. This suggested that the level of (n-6) PUFA, which was considerably lower in the FPO diet than in the control diet, could act on locomotion through an effect on striatal dopaminergic function, whereas the high level of (n-3) PUFA could act on cortical dopaminergic function.
The Journal of Neuroscience, 2001
Contrast media & molecular imaging, 2018
In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging h... more In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, inc...
Molecular imaging
Excitotoxicity leads to an inflammatory reaction involving an overexpression of: translocator pro... more Excitotoxicity leads to an inflammatory reaction involving an overexpression of: translocator protein 18 kDa (TSPO) in cerebral microglia and astrocytes. Therefore, we performed ex vivo explorations with [(125)]-CLINDE, a TSPO-specific radioligand, to follow the time course of TSPO expression, in parallel with lesion progression, over 90 days after induction of cerebral excitotoxicity in rats intrastriatally injected with quinolinic acid. Biodistribution data showed a significant increase in CLINDE uptake on the injured side from 1 days postlesion (dpl); the maximal striatal binding values evidenced a plateau between 7 and 30 dpl. [(125)I]-CLINDE binding was displaced from the lesion by PK11195, suggesting TSPO specificity. These results were confirmed by ex vivo autoradiography. Combined immunohistochemical studies showed a marked increase in microglial expression in the lesion, peaking at 14 dpl, and astrocytic reactivity enhanced at 7 and 14 dpl, whereas a prominent neuronal cell...
International Journal of Nuclear Medicine and Biology, 1986
This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. ... more This report describes the comparison between two adrenal medulla imaging agents, mIBG and I-CPP. Biodistribution demonstrated an early and preferential uptake by both adrenal glands and heart and then storage in the adrenal gland of both agents, however I-CPP is less stable in vivo than mIBG. Reserpine depletion study in rat indicated that the I-CPP and mIBG uptake mechanisms are not similar.
International Journal of Molecular Sciences, 2017
Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wi... more Microglia, as cellular mediators of neuroinflammation, are implicated in the pathogenesis of a wide range of neurodegenerative diseases. Positron emission tomography (PET) imaging of microglia has matured over the last 20 years, through the development of radiopharmaceuticals targeting several molecular biomarkers of microglial activation and, among these, mainly the translocator protein-18 kDa (TSPO). Nevertheless, current limitations of TSPO as a PET microglial biomarker exist, such as low brain density, even in a neurodegenerative setting, expression by other cells than the microglia (astrocytes, peripheral macrophages in the case of blood brain barrier breakdown), genetic polymorphism, inducing a variation for most of TSPO PET radiopharmaceuticals' binding affinity, or similar expression in activated microglia regardless of its polarization (pro-or anti-inflammatory state), and these limitations narrow its potential interest. We overview alternative molecular targets, for which dedicated radiopharmaceuticals have been proposed, including receptors (purinergic receptors P2X7, cannabinoid receptors, α7 and α4β2 nicotinic acetylcholine receptors, adenosine 2A receptor, folate receptor β) and enzymes (cyclooxygenase, nitric oxide synthase, matrix metalloproteinase, β-glucuronidase, and enzymes of the kynurenine pathway), with a particular focus on their respective contribution for the understanding of microglial involvement in neurodegenerative diseases. We discuss opportunities for these potential molecular targets for PET imaging regarding their selectivity for microglia expression and polarization, in relation to the mechanisms by which microglia actively participate in both toxic and neuroprotective actions in brain diseases, and then take into account current clinicians' expectations.
La Revue de Médecine Interne, 2011
Contrast Media & Molecular Imaging, 2017
Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gath... more Peripheral sterile inflammatory diseases (PSIDs) are a heterogeneous group of disorders that gathers several chronic insults involving the cardiovascular, respiratory, gastrointestinal, or musculoskeletal system and wherein inflammation is the cornerstone of the pathophysiology. In PSID, timely characterization and localization of inflammatoryfociare crucial for an adequate care for patients. In brain diseases,in vivopositron emission tomography (PET) exploration of inflammation has matured over the last 20 years, through the development of radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO) as molecular biomarkers of activated microglia. Recently, TSPO has been introduced as a possible molecular target for PSIDs PET imaging, making this protein a potential biomarker to address disease heterogeneity, to assist in patient stratification, and to contribute to predicting treatment response. In this review, we summarized the major research advances recently made in the...
International Journal of Molecular Sciences, 2017
In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positro... more In vivo exploration of activated microglia in neurodegenerative diseases is achievable by Positron Emission Tomography (PET) imaging, using dedicated radiopharmaceuticals targeting the translocator protein-18 kDa (TSPO). In this review, we emphasized the major advances made over the last 20 years, thanks to TSPO PET imaging, to define the pathophysiological implication of microglia activation and neuroinflammation in neurodegenerative diseases, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. The extent and upregulation of TSPO as a molecular biomarker of activated microglia in the human brain is now widely documented in these pathologies, but its significance, and especially its protective or deleterious action regarding the disease's stage, remains under debate. Thus, we exposed new and plausible suggestions to enhance the contribution of TSPO PET imaging for biomedical research by exploring microglia's role and interactions with other cells in brain parenchyma. Multiplex approaches, associating TSPO PET radiopharmaceuticals with other biomarkers (PET imaging of cellular metabolism, neurotransmission or abnormal protein aggregates, but also other imaging modalities, and peripheral cytokine levels measurement and/or metabolomics analysis) was considered. Finally, the actual clinical impact of TSPO PET imaging as a routine biomarker of neuroinflammation was put into perspective regarding the current development of diagnostic and therapeutic strategies for neurodegenerative diseases.
Frontiers in Medicine, 2017
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 28, 2016
Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the ex... more Subjective cognitive decline (SCD) could indicate preclinical Alzheimer's disease, but the existing literature is confounded by heterogeneous approaches to studying SCD. We assessed the differential cognitive, affective, and neuroimaging correlates of two aspects of SCD: reporting high cognitive difficulties on a self-rated questionnaire versus consulting at a memory clinic. We compared 28 patients from a memory clinic with isolated SCD, 35 community-recruited elders with similarly high levels of self-reported cognitive difficulties, and 35 community-recruited controls with low self-reported cognitive difficulties. Increased anxiety and β-amyloid deposition were observed in both groups with high self-reported difficulties, whereas subclinical depression and (hippocampal) atrophy were specifically associated with medical help seeking. Cognitive tests showed no group differences. These results further validate the concept of SCD in both community- and clinic-based groups. Yet, rec...
Journal of Pharmacology and Experimental Therapeutics, Jul 1, 1997
N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)nortropane (β-CDIT), a new iodi... more N-(3-Iodoprop-2 E -enyl)-2β-carbomethoxy-3β-(3′,4′-dichlorophenyl)nortropane (β-CDIT), a new iodinated tropane derivative, has been synthesized and radiolabeled with iodine. [ 125 I]β-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [ 125 I]β-CDIT bound to a single high-affinity site. The K d value was 0.18 ± 0.07 nM, and the corresponding B max value was 500 ± 80 fmol/mg of protein. The pharmacological profile of specific [ 125 I]β-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [ 3 H]paroxetine and [ 3 H]nisoxetine showed a very low affinity of β-CDIT for the 5-hydroxytryptamine ( K i = 50 nM) and norepinephrine ( K i = 500 nM) transporters compared with β-CIT (corresponding K i values were 3 and 80 nM). In contrast, the competition of β-CDIT with [ 3 H]GBR 12935 in the striatal region ( K i = 29 nM) was of the same order of value as for β-CIT ( K i = 27.5 nM). Behavioral experiments in mice showed that both β-CDIT and β-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [ 125 I]β-CDIT demonstrated high densities of [ 125 I]β-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [ 125 I]β-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
Nuclear Medicine and Biology, 2008