Search

Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action.

Abstract Resolving genomes at haplotype level is crucial for understanding the evolutionary history of polyploid species and for designing advanced breeding strategies. Polyploid phasing still presents considerable challenges, especially in regions of collapsing haplotypes.We present WhatsHap polyphase, a novel two-stage approach that addresses these challenges by (i) clustering reads and (ii) threading the haplotypes through the clusters. Our method outperforms the state-of-the-art in terms of phasing quality. Using a real tetraploid potato dataset, we demonstrate how to assemble local genomic regions of interest at the haplotype level. Our algorithm is implemented as part of the widely used open source tool WhatsHap.

Abstract Background Extra-cellular roles of Tat might be the main cause of maintenance of HIV-1 infected CD4 T cells or reservoir cells. We developed a synthetic vaccine based on a Tat variant of 101 residues called Tat Oyi, which was identified in HIV infected patients in Africa who did not progress to AIDS. We compared, using rabbits, different adjuvants authorized for human use to test on ELISA the recognition of Tat variants from the five main HIV-1 subtypes. A formulation was tested on macaques followed by a SHIV challenge with a European strain. Results Tat Oyi with Montanide or Calcium Phosphate gave rabbit sera able to recognize all Tat variants. Five on seven Tat Oyi vaccinated macaques showed a better control of viremia compared to control macaques and an increase of CD8 T cells was observed only on Tat Oyi vaccinated macaques. Reservoir cells were not detectable at 56 days post-challenge in all Tat Oyi vaccinated macaques but not in the controls. Conclusion The Tat Oyi vaccine should be efficient worldwide. No toxicity was observed on rabbits and macaques. We show in vivo that antibodies against Tat could restore the cellular immunity and make it possible the elimination of reservoir cells.

Abstract Background HIV infection and progression to AIDS is characterized by the depletion of T cells, which could be due, in part, to apoptosis mediated by the extra-cellular HIV-encoded Tat protein as a consequence of Tat binding to tubulin. Microtubules are tubulin polymers that are essential for cell structure and division. Molecules that target microtubules induce apoptosis and are potent anti-cancer drugs. We studied the effect on tubulin polymerization of three Tat variants: Tat HxB2 and Tat Eli from patients who are rapid progressors (RP) and Tat Oyi from highly exposed but persistently seronegative (HEPS) patients. We compared the effect on tubulin polymerization of these Tat variants and peptides corresponding to different parts of the Tat sequence, with paclitaxel, an anti-cancer drug that targets microtubules. Results We show that Tat, and specifically, residues 38–72, directly enhance tubulin polymerization. We demonstrate that Tat could also directly trigger the mitochondrial pathway to induce T cell apoptosis, as shown in vitro by the release of cytochrome c from isolated mitochondria. Conclusions These results show that Tat directly acts on microtubule polymerization and provide insights into the mechanism of T cell apoptosis mediated by extra-cellular Tat.

Background: Estimates suggest that approximatively 25% of the world population will be overweight in 2025. Better understanding of the pathophysiology of obesity will help to develop future therapeutics. Serotonin subtype 6 receptors (5-HT 6 ) have been shown to be critically involved in appetite reduction and weight loss. However, it is not known if the pathological cascade triggered by obesity modifies the density of 5-HT 6 receptors in the brain., Methods: Influence of diet-induced obesity (DIO) in Wistar rats was explored using MRI (whole-body fat) and PET ([ 18 F]2FNQ1P as a specific 5-HT 6 radiotracer). The primary goal was to monitor the 5-HT 6 receptor density before and after a 10-week diet (DIO group). The secondary goal was to compare 5-HT 6 receptor densities between DIO group, Wistar control diet group, Zucker rats (with genetic obesity) and Zucker lean strain rats., Results: Wistar rats fed with high-fat diet showed higher body fat gain than Wistar control diet rats on MRI. [ 18 F]2FNQ1P PET analysis highlighted significant clusters of voxels (located in hippocampus, striatum, cingulate, temporal cortex and brainstem) with increased binding after high-fat diet (p < 0.05, FWE corrected)., Conclusion: This study sheds a new light on the influence of high-fat diet on 5-HT 6 receptors. This study also positions [ 18 F]2FNQ1P PET as an innovative tool to explore neuronal consequences of obesity or eating disorder pathophysiology., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: All experiments were carried out under a protocol approved by the local review board (“Comité d’éthique pour l’Expérimentation Animale Neurosciences Lyon”, registration code: C2EA—42), authorized by the French Ministry of Higher Education and Research (no. 25505-2020052514313066V6, and were in accordance with European directives on the protection and use of laboratory animals (Council Directive 2010/63/UE; French decree 2013-118)., (© 2024. The Author(s).)

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in many physiological and pathological mechanisms through its numerous receptors. Among these, the 5-HT 2B receptor is known to play a key role in multiple brain disorders but remains poorly understood. Positron emission tomography (PET) can contribute to a better understanding of pathophysiological mechanisms regulated by the 5-HT 2B receptor. To develop the first PET radiotracer for the 5-HT 2B receptor, RS-127445, a well-known 5-HT 2B receptor antagonist, was labeled with fluorine-18. [ 18 F]RS-127445 was synthesized in a high radiochemical purity and with a good molar activity and radiochemical yield. Preliminary PET scans in rats showed good brain penetration of [ 18 F]RS-127445. However, competition experiments and in vitro autoradiography showed high non-specific binding, especially to brain white matter., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: [ 18 F]F13640 is a new PET radiopharmaceutical for brain molecular imaging of serotonin 5-HT 1A receptors. Since we intend to use this radiopharmaceutical in psychiatric studies, it is crucial to establish possible sensitivity modification of 5-HT 1A receptors availability during an acute stress exposure. In this study, we first assessed the cerebrometabolic effects of a new animal model of stress with [ 18 F]FDG and then proceeded to test for effects of this model on the cerebral binding of [ 18 F]F13640, a 5-HT 1A receptors PET radiopharmaceutical., Methods: Four groups of male Sprague-Dawley were used to identify the optimal model: "stressed group" (n = 10), "post-traumatic stress disorder (PTSD) group" (n = 9) and "restraint group" (n = 8), compared with a control group (n = 8). All rats performed neuroimaging [ 18 F]FDG μPET-CT to decipher which model was the most appropriate to test effects of stress on radiotracer binding. Subsequently, a group of rats (n = 10) underwent two PET imaging acquisitions (baseline and PTSD condition) using the PET radiopharmaceutical [ 18 F]F13640 to assess influence of stress on its binding. Voxel-based analysis was performed to assess [ 18 F]FDG or [ 18 F]F13640 changes., Results: In [ 18 F]FDG experiments, the PTSD group showed a pattern of cerebrometabolic activation in various brain regions previously implicated in stress (amygdala, perirhinal cortex, olfactory bulb and caudate). [ 18 F]F13640 PET scans showed increased radiotracer binding in the PTSD condition in caudate nucleus and brainstem., Conclusions: The present study demonstrated stress-induced cerebrometabolic activation or inhibition of various brain regions involved in stress model. Applying this model to our radiotracer, [ 18 F]F13640 showed few influence of stress on its binding. This will enable to rule out any confounding effect of stress during imaging studies., Competing Interests: Declaration of competing interest Nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

At present, spinal cord imaging primarily uses magnetic resonance imaging (MRI) or computed tomography (CT), but the greater sensitivity of positron emission tomography (PET) techniques and the development of new radiotracers are paving the way for a new approach. The substantial rise in publications on PET radiotracers for spinal cord exploration indicates a growing interest in the functional and molecular imaging of this organ. The present review aimed to provide an overview of the various radiotracers used in this indication, in preclinical and clinical settings. Firstly, we outline spinal cord anatomy and associated target pathologies. Secondly, we present the state-of-the-art of spinal cord imaging techniques used in clinical practice, with their respective strengths and limitations. Thirdly, we summarize the literature on radiotracers employed in functional PET imaging of the spinal cord. In conclusion, we propose criteria for an ideal radiotracer for molecular spinal cord imaging, emphasizing the relevance of multimodal hybrid cameras, and particularly the benefits of PET-MRI integration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: MRI is the main imaging modality for pediatric brain tumors, but amino acid PET can provide additional information. Simultaneous PET-MRI acquisition allows to fully assess the tumor and lower the radiation exposure. Although symptomatic posterior fossa tumors are typically resected, the patient management is evolving and will benefit from an improved preoperative tumor characterization. We aimed to explore, in children with newly diagnosed posterior fossa tumor, the complementarity of the information provided by amino acid PET and MRI parameters and the correlation to histopathological results., Patients and Methods: Children with a newly diagnosed posterior fossa tumor prospectively underwent a preoperative 11 C-methionine (MET) PET-MRI. Images were assessed visually and semiquantitatively. Using correlation, minimum apparent diffusion coefficient (ADC min ) and contrast enhancement were compared with MET SUV max . The diameter of the enhancing lesions was compared with metabolic tumoral volume. Lesions were classified according to the 2021 World Health Organization (WHO) classification., Results: Ten children were included 4 pilocytic astrocytomas, 2 medulloblastomas, 1 ganglioglioma, 1 central nervous system embryonal tumor, and 1 schwannoma. All lesions showed visually increased MET uptake. A negative moderate correlation was found between ADC min and SUV max values ( r = -0.39). Mean SUV max was 3.8 (range, 3.3-4.2) in WHO grade 4 versus 2.5 (range, 1.7-3.0) in WHO grade 1 lesions. A positive moderate correlation was found between metabolic tumoral volume and diameter values ( r = 0.34). There was no correlation between SUV max and contrast enhancement intensity ( r = -0.15)., Conclusions: Preoperative 11 C-MET PET and MRI could provide complementary information to characterize pediatric infratentorial tumors., Competing Interests: Conflicts of interest and sources of funding: The authors have no conflicts of interest to declare. P.-A.B. received funding from the Hospices Civils de Lyon Foundation, Banque Populaire AURA, and the Flavien Foundation for their financial support., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The interest in new 5-HT₆ agents stems from their ability to modulate cognition processing, food motivation and anxiety-like behaviors. While these findings come primarily from rodent studies, no studies on primates have been published. Furthermore, our understanding of where and how they act in the brain remains limited. Although the striatum is involved in all of these processes and expresses the highest levels of 5-HT₆ receptors, few studies have focused on it. We thus hypothesized that 5-HT 6 receptor blockade would influence food motivation and modulate behavioral expression in non-human primates through striatal 5-HT 6 receptors. This study thus aimed to determine the effects of acute administration of the SB-258585 selective 5-HT 6 receptor antagonist on the feeding motivation and behaviors of six male macaques. Additionally, we investigated potential 5-HT 6 targets using PET imaging to measure 5-HT 6 receptor occupancy throughout the brain and striatal subregions. We used a food-choice task paired with spontaneous behavioral observations, checking 5-HT 6 receptor occupancy with the specific PET imaging [ 18 F]2FNQ1P radioligand. We demonstrated, for the first time in non-human primates, that modulation of 5-HT 6 transmission, most likely through the striatum (the putamen and caudate nucleus), significantly reduces food motivation while exhibiting variable, weaker effects on behavior. While these results are consistent with the literature showing a decrease in food intake in rodents and proposing that 5-HT 6 receptor antagonists can be used in obesity treatment, they question the antagonists' anxiolytic potential., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson's disease, but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluated two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson's disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI; and the density of α2-adrenergic receptors (ARs) with PET using 11C-yohimbine. Thirty patients with Parkinson's disease and 30 age- and sex-matched healthy control subjects were included. The characteristics of the patients' symptoms were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared with controls and diminished 11C-yohimbine binding in widespread cortical regions, including the motor cortex, as well as in the insula, thalamus and putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-AR availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These results highlight a multifaceted alteration of the noradrenergic system in Parkinson's disease since locus coeruleus and α2-AR degeneration were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunction that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson's disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Experimentally, ultra-protective ventilation (UPV, tidal volumes [V T ] < 4 mL.kg -1 ) strategies in conjunction with veno-venous extracorporeal membrane oxygenation (VV-ECMO) are associated with lesser ventilator-induced lung injuries (VILI) during acute respiratory distress syndrome (ARDS). However, whether these strategies reduce lung inflammation more effectively than protective ventilation (PV) remains unclear. We aimed to demonstrate that a UPV strategy decreases acute lung inflammation in comparison with PV in an experimental swine model of ARDS., Methods: ARDS was induced by tracheal instillation of chlorhydric acid in sedated and paralyzed animals under mechanical ventilation. Animals were randomized to receive either UPV (V T 1 mL.kg -1 , positive end-expiration pressure [PEEP] set to obtain plateau pressure between 20 and 25 cmH 2 O and respiratory rate [RR] at 5 min -1 under VV-ECMO) or PV (V T 6 mL.kg -1 , PEEP set to obtain plateau pressure between 28 and 30 cmH 2 O and RR at 25 min -1 ) during 4 h. After 4 h, a positron emission tomography with [ 11 C](R)-PK11195 (ligand to TSPO-bearing macrophages) injection was realized, coupled with quantitative computerized tomography (CT). Pharmacokinetic multicompartment models were used to quantify regional [ 11 C](R)-PK11195 lung uptake. [ 11 C](R)-PK11195 lung uptake and CT-derived respiratory variables were studied regionally across eight lung regions distributed along the antero-posterior axis., Results: Five pigs were randomized to each study group. Arterial O 2 partial pressure to inspired O 2 fraction were not significantly different between study groups after experimental ARDS induction (75 [68-80] mmHg in a PV group vs. 87 [69-133] mmHg in a UPV group, p  = 0.20). Compared to PV animals, UPV animals exhibited a significant decrease in the regional non-aerated compartment in the posterior lung levels, in mechanical power, and in regional dynamic strain and no statistical difference in tidal hyperinflation after 4 h. UPV animals had a significantly lower [ 11 C](R)-PK11195 uptake, compared to PV animals (non-displaceable binding potential 0.35 [IQR, 0.20-0.59] in UPV animals and 1.01 [IQR, 0.75-1.59] in PV animals, p  = 0.01). Regional [ 11 C](R)-PK11195 uptake was independently associated with the interaction of regional tidal hyperinflation and regional lung compliance., Conclusion: In an experimental model of ARDS, 4 h of UPV strategy significantly decreased lung inflammation, in relation to the control of V T -derived determinants of VILI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Deniel, Dhelft, Lancelot, Orkisz, Roux, Mouton, Benzerdjeb, Richard and Bitker.)

Non-human primate studies are unique in translational research, especially in neurosciences where neuroimaging approaches are the preferred methods used for cross-species comparative neurosciences. In this regard, neuroimaging database development and sharing are encouraged to increase the number of subjects available to the community, while limiting the number of animals used in research. Here we present a simultaneous positron emission tomography (PET)/magnetic resonance (MR) dataset of 20 Macaca fascicularis images structured according to the Brain Imaging Data Structure standards. This database contains multiple MR imaging sequences (anatomical, diffusion and perfusion imaging notably), as well as PET perfusion and inflammation imaging using respectively [ 15 O]H 2 O and [ 11 C]PK11195 radiotracers. We describe the pipeline method to assemble baseline data from various cohorts and qualitatively assess all the data using signal-to-noise and contrast-to-noise ratios as well as the median of intensity and the pseudo-noise-equivalent-count rate (dynamic and at maximum) for PET data. Our study provides a detailed example for quality control integration in preclinical and translational PET/MR studies with the aim of increasing reproducibility. The PREMISE database is stored and available through the PRIME-DE consortium repository., (© 2023. The Author(s).)

The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [ 11 C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20-50) to perform direct quantification of regional alpha 2 adrenergic receptors' (α 2 -ARs) availability in the living human brain. The global map shows the highest [ 11 C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [ 11 C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α 2 -ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α 2 -ARs is suspected.

Purpose: F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT 1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [ 18 F]F13640 binds preferentially to functional 5-HT 1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT 1A receptors by [ 18 F]F13640 in humans and describe a simplified model for its quantification., Methods: PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test-retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF)., Results: [ 18 F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test-retest parameters and the prolonged binding kinetics of [ 18 F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions., Conclusion: The favorable brain labeling and kinetic profile of [ 18 F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT 1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [ 18 F]F13640's kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry., Trial Registration: Trial Registration EudraCT 2017-002,722-21., (© 2023. The Author(s).)

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [ 11 C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [ 11 C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [ 11 C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [ 15 O 2 ]H 2 OPET imaging. [ 11 C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation., (© 2023. The Author(s).)

Whether prone positioning (PP) modulates acute lung inflammation by the modulation of biomechanical forces of ventilator-induced lung injuries (VILIs) remains unclear. We aimed to demonstrate that PP decreases acute lung inflammation in animals with experimental acute respiratory distress syndrome (ARDS). Animals were under general anesthesia and protective ventilation (tidal volume 6 mL·kg -1 , PEEP 5 cmH 2 O). ARDS was induced by intratracheal instillation of chlorohydric acid. Animals were then randomized to PP, or to supine position (SP). After 4 h, a positron emission tomography (PET) acquisition with [ 11 C](R)-PK11195 was performed coupled with computerized tomography (CT) acquisitions, allowing the CT quantification of VILI-associated parameters. [ 11 C](R)-PK11195 lung uptake was quantified using pharmacokinetic multicompartment models. Analyses were performed on eight lung sections distributed along the antero-posterior dimension. Six animals were randomized to PP, five to SP (median [Formula: see text]/[Formula: see text] [interquartile range]: 164 [102-269] mmHg). The normally aerated compartment was significantly redistributed to the posterior lung regions of animals in PP, compared with SP. Dynamic strain was significantly increased in posterior regions of SP animals, compared with PP. After 4 h, animals in PP had a significantly lower uptake of [ 11 C](R)-PK11195, compared with SP. [ 11 C](R)-PK11195 regional uptake was independently associated with the study group, dynamic strain, tidal hyperinflation, and regional respiratory system compliance in multivariate analysis. In an experimental model of ARDS, 4 h of PP significantly decreased acute lung inflammation assessed with PET. The beneficial impact of PP on acute lung inflammation was consecutive to the combination of decreased biomechanical forces and changes in the respiratory system mechanics. NEW & NOTEWORTHY Prone position decreases acute lung macrophage inflammation quantified in vivo with [ 11 C](R)-PK11195 positron emission tomography in an experimental acute respiratory distress syndrome. Regional macrophage inflammation is maximal in the most anterior and posterior lung section of supine animals, in relation with increased regional tidal strain and hyperinflation, and reduced regional lung compliance.

Purpose: Imaging of acute lung inflammation is pivotal to evaluate innovative ventilation strategies. We aimed to develop and validate a three-tissue compartment kinetic model (3TCM) of [ 11 C](R)-PK11195 lung uptake in experimental acute respiratory distress syndrome (ARDS) to help quantify macrophagic inflammation, while accounting for the impact of its non-specific and irreversible uptake in lung tissues., Material and Methods: We analyzed the data of 38 positron emission tomography (PET) studies performed in 21 swine with or without experimental ARDS, receiving general anesthesia and mechanical ventilation. Model input function was a plasma, metabolite-corrected, image-derived input function measured in the main pulmonary artery. Regional lung analysis consisted in applying both the 3TCM and the two-tissue compartment model (2TCM); in each region, the best model was selected using a selection algorithm with a goodness-of-fit criterion. Regional best model binding potentials (BP ND ) were compared to lung macrophage presence, semi-quantified in pathology., Results: The 3TCM was preferred in 142 lung regions (62%, 95% confidence interval: 56 to 69%). BP ND determined by the 2TCM was significantly higher than the value computed with the 3TCM (overall median with interquartile range: 0.81 [0.44-1.33] vs. 0.60 [0.34-0.94], p < 0.02). Regional macrophage score was significantly associated with the best model BP ND (p = 0.03). Regional BP ND was significantly increased in the hyperinflated lung compartment, compared to the normally aerated one (median with interquartile range: 0.8 [0.6-1.7] vs. 0.6 [0.3-0.8], p = 0.03)., Conclusion: To assess the intensity and spatial distribution of acute macrophagic lung inflammation in the context of experimental ARDS with mechanical ventilation, PET quantification of [ 11 C](R)-PK11195 lung uptake was significantly improved in most lung regions using the 3TCM. This new methodology offers the opportunity to non-invasively evaluate innovative ventilatory strategies aiming at controlling acute lung inflammation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: De novo Parkinson's disease (PD) patients with apathy exhibit prominent limbic serotonergic dysfunction and microstructural disarray. Whether this distinctive lesion profile at diagnosis entails different prognosis remains unknown., Objectives: To investigate the progression of dopaminergic and serotonergic dysfunction and their relation to motor and nonmotor impairment in PD patients with or without apathy at diagnosis., Methods: Thirteen de novo apathetic and 13 nonapathetic PD patients were recruited in a longitudinal double-tracer positron emission tomography cohort study. We quantified the progression of presynaptic dopaminergic and serotonergic pathology using [ 11 C]PE2I for dopamine transporter and [ 11 C]DASB for serotonin transporter at baseline and 3 to 5 years later, using linear mixed-effect models and mediation analysis to compare the longitudinal evolution between groups for clinical impairment and region-of-interest-based analysis., Results: After the initiation of dopamine replacement therapy, apathy, depression, and anxiety improved at follow-up in patients with apathy at diagnosis (n = 10) to the level of patients without apathy (n = 11). Patients had similar progression of motor impairment, whereas mild impulsive behaviors developed in both groups. Striato-pallidal and mesocorticolimbic presynaptic dopaminergic loss progressed similarly in both groups, as did serotonergic pathology in the putamen, caudate nucleus, and pallidum. Contrastingly, serotonergic innervation selectively increased in the ventral striatum and anterior cingulate cortex in apathetic patients, contributing to the reversal of apathy besides dopamine replacement therapy., Conclusion: Patients suffering from apathy at diagnosis exhibit compensatory changes in limbic serotonergic innervation within 5 years of diagnosis, with promising evidence that serotonergic plasticity contributes to the reversal of apathy. The relationship between serotonergic plasticity and dopaminergic treatments warrants further longitudinal investigations. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Previous work introduced the [ 11 C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [ 11 C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [ 11 C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap., Methods: Thirteen healthy humans underwent two [ 11 C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested., Results: We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTM CC (r 2 =0.94). Test-retest showed that the SRTM CC is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTM CERWM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTM CC , regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis., Conclusion: The results add experimental support for the suitability of [ 11 C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare that are relevant to the content of this article., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

We present a database of cerebral PET FDG and anatomical MRI for 37 normal adult human subjects (CERMEP-IDB-MRXFDG). Thirty-nine participants underwent static [ 18 F]FDG PET/CT and MRI, resulting in [ 18 F]FDG PET, T1 MPRAGE MRI, FLAIR MRI, and CT images. Two participants were excluded after visual quality control. We describe the acquisition parameters, the image processing pipeline and provide participants' individual demographics (mean age 38 ± 11.5 years, range 23-65, 20 women). Volumetric analysis of the 37 T1 MRIs showed results in line with the literature. A leave-one-out assessment of the 37 FDG images using Statistical Parametric Mapping (SPM) yielded a low number of false positives after exclusion of artefacts. The database is stored in three different formats, following the BIDS common specification: (1) DICOM (data not processed), (2) NIFTI (multimodal images coregistered to PET subject space), (3) NIFTI normalized (images normalized to MNI space). Bona fide researchers can request access to the database via a short form., (© 2021. The Author(s).)

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., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia ( Macaca fascicularis ) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

In an acute ischaemic stroke, understanding the dynamics of blood-brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood-brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood-brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood-brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX ® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant K trans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10 -3  min -1 , respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10 -3  min -1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, K trans for both Gd-DOTA and AGuIX ® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10 -3  min -1 for Gd-DOTA and AGuIX ® nanoparticles, respectively. With AGuIX ® nanoparticles, K trans also increased within the ischaemic growth areas, suggesting added value for AGuIX ® . Finally, K trans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n  = 7) compared to placebo ( n  = 5). K trans quantification with AGuIX ® nanoparticles can monitor early blood-brain barrier damage and treatment effect in ischaemic stroke after reperfusion., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [ 18 F]2FNQ1P, a new PET radiotracer of 5-HT 6 receptors, in rat, pig, non-human primate and human tissues. The 5-HT 6 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 [ 18 F]2FNQ1P in cerebral regions with high 5-HT 6 receptor density. Binding was blocked by addition of SB258585 as a specific antagonist. Binding assays provided K D and B max values of respectively 1.34 nM and 0.03 pmol·mg - 1 in rat, 0.60 nM and 0.04 pmol·mg - 1 in pig, 1.38 nM and 0.07 pmol·mg - 1 in non-human primate, and 1.39 nM and 0.15 pmol·mg - 1 in human caudate nucleus. In rat brain, the proportion of unmetabolized [ 18 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 [ 18 F]2FNQ1P is a specific radiotracer for molecular imaging of 5-HT 6 receptors and suggest that it could be used as a radiopharmaceutical in humans., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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 ([ 18 F]FDG), dopamine neurotransmission ([ 11 C]raclopride, [ 11 C]PE2I) and serotonin neurotransmission ([ 18 F]MPPF, [ 11 C]DASB). For all radiotracers, except [ 18 F]FDG, PET data were analyzed with a MRI-based VOI method and a voxel-based analysis., Results: MicroPET data showed a decrease in [ 11 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 2 receptors. The increase in [ 18 F]MPPF uptake in M83 vs WT and KO mice indicates overexpression of 5-HT 1A 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 2 receptor, whereas aggregated α-syn leads to overexpression of 5-HT 1A receptor, as a pathophysiological signature., (© 2018 John Wiley & Sons Ltd.)

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.

The accumulation of aggregated alpha-synuclein ( α -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 α -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 [ 11 C]BF-227 as a promising radiotracer for monitoring intracellular α -syn deposition in MSA patients. We sought to confirm the binding of this radiotracer to α -syn using state-of-the-art autoradiography. Medulla sections were obtained from 9 MSA patients and 9 controls (London Neurodegenerative Diseases Brain Bank). [ 18 F]BF-227, chemically identical to [ 11 C]BF-227, was used at nanomolar concentrations to perform in vitro autoradiography assays. Autoradiograms were superimposed on fluorescent staining from the conformational anti- α -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 [ 18 F]BF-227 to CGI at concentrations typically achieved in PET experiments.

A 23-year-old man, with no relevant medical history, presented with inflammatory peripheral and axial polyarthritis, wrist pain, and persistent low-grade fever for the past 4 months. A bone scintigraphy showed intense periosteal early and delayed uptake in long bones, with normal uptake in the spine, pelvis, and rib cage, and no clear focus of hypermetabolism. CT scan revealed a mediastinal mass. A biopsy of the mass demonstrated Hodgkin lymphoma with bulky disease. This paraneoplastic syndrome as the first sign of intrathoracic Hodgkin's disease is rare.

Introduction: Preclinical in vivo imaging requires precise and reproducible delineation of brain structures. Manual segmentation is time consuming and operator dependent. Automated segmentation as usually performed via single atlas registration fails to account for anatomo-physiological variability. We present, evaluate, and make available a multi-atlas approach for automatically segmenting rat brain MRI and extracting PET activies., Methods: High-resolution 7T 2DT2 MR images of 12 Sprague-Dawley rat brains were manually segmented into 27-VOI label volumes using detailed protocols. Automated methods were developed with 7/12 atlas datasets, i.e. the MRIs and their associated label volumes. MRIs were registered to a common space, where an MRI template and a maximum probability atlas were created. Three automated methods were tested: 1/registering individual MRIs to the template, and using a single atlas (SA), 2/using the maximum probability atlas (MP), and 3/registering the MRIs from the multi-atlas dataset to an individual MRI, propagating the label volumes and fusing them in individual MRI space (propagation & fusion, PF). Evaluation was performed on the five remaining rats which additionally underwent [18F]FDG PET. Automated and manual segmentations were compared for morphometric performance (assessed by comparing volume bias and Dice overlap index) and functional performance (evaluated by comparing extracted PET measures)., Results: Only the SA method showed volume bias. Dice indices were significantly different between methods (PF>MP>SA). PET regional measures were more accurate with multi-atlas methods than with SA method., Conclusions: Multi-atlas methods outperform SA for automated anatomical brain segmentation and PET measure's extraction. They perform comparably to manual segmentation for FDG-PET quantification. Multi-atlas methods are suitable for rapid reproducible VOI analyses.

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.

Nonosseous uptakes are occasionally found on bone scintigraphy. Most of them are easily explained by current pathophysiological mechanisms (metastatic calcifications, metabolic process, or extravascular accumulation of radiopharmaceutical) or current artifacts. Other unusual findings are still unexplained. We report 1 didactic case of incidental gallbladder uptake on bone scan. Additional single-photon emission computed tomography-computed tomography (SPECT/CT) imaging was performed to better characterize abnormal location. The significance of this serendipitous uptake is not clearly established. This finding could be due to altered distribution induced by the chemotherapy regimen and is not the result of intrinsic gallbladder disease.

Unlabelled: PET brain imaging of the serotonin 1A (5-hydroxytryptamine 1A [5-HT(1A)]) receptor has been widely used in clinical studies. Currently, only a few well-validated radiolabeled antagonist tracers are available for in vivo imaging of this central receptor. 5-HT(1A) receptors exist in high- and low-affinity states, depending on their coupling to G proteins. Agonists bind preferentially to receptors in the high-affinity state and thereby could provide a measure of functional 5-HT(1A) receptors. Therefore, it is of great interest to develop an (18)F-labeled full agonist 5-HT(1A) receptor radiotracer. In this study, we radiolabeled the high-affinity 5-HT(1A) receptor agonist (18)F-F13714 and investigated its potential as a PET tracer., Methods: F13714 nitro precursor was synthesized and radiolabeled via a fluoronucleophilic substitution. In vitro binding assays were performed using established protocols. Radiopharmacologic evaluations included in vitro autoradiography in rat brain and PET scans on anesthetized cats., Results: The chemical and radiochemical purities of (18)F-F13714 were greater than 98%. F13714 has a high affinity (0.1 nM) and selectivity for 5-HT(1A) receptors. In vitro (18)F-F13714 binding in rats was consistent with the known 5-HT(1A) receptors distribution (hippocampus and cortical areas) and was particularly high in the dorsal raphe. In vitro binding of (18)F-F13714 was blocked in a dose-dependent fashion by WAY100635, the prototypical 5-HT(1A) antagonist, and by the endogenous agonist, serotonin (5-HT). Addition of Gpp(NH)p also inhibited in vitro (18)F-F13714 binding, consistent with a preferential binding of the compound to G-protein-coupled receptors. Ex vivo tissue measurements in rat revealed an absence of brain radioactive metabolites. In vivo studies showed that the radiotracer entered the cat brain readily and displayed a preferential labeling of 5-HT(1A) receptors located in cingulate cortex. In vivo labeling was prevented by preinjection of WAY100635., Conclusion: (18)F-F13714 is a radiofluorinated agonist that presents suitable characteristics for probing the high-affinity states of the 5-HT(1A) receptors in vitro and in vivo. Thus, it is a promising tool for investigation of 5-HT(1A) agonist binding in the living human brain.

Small-animal positron emission tomography (PET) is a preclinical imaging method that uses pharmacologically or biochemically active compounds labelled with short-lived positron-emitting radionuclides. This non-invasive nuclear medicine technique requiring animal-dedicated PET cameras (microPET) enables in vivo measurements of physiological processes, biochemical pathways and neurotransmitters. It therefore has a role in studying the pathophysiology and pharmacology of the brain. Moreover, there is increasing evidence that microPET imaging can accelerate drug development by revealing early information regarding biomarkers of pathophysiology or drug mechanisms and cerebral bioavailability. This review presents the potential contribution of microPET in basic neuropharmacology, illustrating its recent contributions and methodological specificities as well as highlighting its limits and constraints. In addition, we aim to encourage the use of PET molecular imaging in basic neuropharmacology to complement other preclinical approaches., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objectives: Radioisotopes that emit beta radiation are used for the treatment of hepatocellular carcinoma, of arthritic patients (radiosynovectomy) and treatment of bone metastases with, respectively, I-labelled lipiodol, colloidal citrate of Y or and Sm-labelled EDTMP. Radiation energy of these radioisotopes that emit beta or beta and gamma radiation (from 300 to 2000 keV) leads to an increase in radiation dose received by nuclear medicine staff. In this paper we focused on clinical and laboratory staff exposure during these types of metabolic radiation therapies., Methods: Cylindrical LiF thermoluminescence dosimeters were used to measure radiation-related whole-body doses (WBDs) and finger doses of the clinical staff., Results: Exposure of the two radiopharmacists and three nurses taking part in I-labelled lipiodol, Y-colloid and Sm-EDTMP therapies, for 12 months in succession, were 146 microSv and 750 microSv, respectively, considering WBD, and 14.6 mSv and 6.5 mSv, respectively, considering finger doses. Extrapolated annual exposures (six radiosynovectomies per year) for the rheumatologists were estimated to be 21 microSv (WBD) and 13.2 mSv (finger dose). Extrapolated annual WBDs and finger doses (25 I-labelled lipiodol treatments per year) for radiologists were estimated to 165 microSv and 3.8 microSv, respectively., Conclusion: Fortunately, these doses were always lower than the limits reported in the European Directive EURATOM 96/29 05/13/1996 (WBD <20 mSv.year; finger dose: 500 mSv.year) but have to be added to those relative to other metabolic radiotherapies such as radioiodine treatments and new metabolic radiotherapies (Y-conjugated peptides or antibodies). Nevertheless, the global exposure of medical staff involved in all these clinical practices justifies dosimetry studies to validate protocols and radiation protection devices for each institution.