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The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.

•[18F]F13640 is a novel PET radiopharmaceutical.•[18F]F13640 is a selective agonist for serotonin 1A receptors.•Short static scan enables accurate and reproducible SUVr quantification.•[18F]F13640 is ready for imaging functional 5-HT1A receptors in clinic. F13640 is a highly selective serotonin 5-HT1A receptor ligand with agonist properties identified as a PET radiopharmaceutical candidate. In previous work, we showed the possibility to use long dynamic PET acquisition (225 min) combined with simplified kinetic modelling for [18F]F13640 quantification. In this work, we assessed the feasibility of static acquisition and quantification using standardized uptake value ratio (SUVR) as an alternative. Test-retest PET-MRI scans of 225 min were conducted in eight healthy male volunteers. For 17 brain regions, distribution volume ratios (DVR) were calculated from the whole kinetics using Logan plot modelling method with the cerebellum white matter as reference region. For the same regions, SUVR were also calculated from static images, for four 20-minute and four 10-minute time-intervals at various time of uptake. Reliability between SUVR and DVR measures were studied, and test-retest parameters were assessed between PET sessions for each time-interval. Reproducibility of measures of SUVR compared to DVR were excellent, whatever the time interval (p < 0.001). For the 20-min. time-intervals, SUVR150–170 showed the best reproducibility and correlation parameters (R2 = 0.95 ± 0.03, intercept = 0.06 ± 0.02, slope = 0.95 ± 0.01). As well, for the 10-min. time-intervals, SUVR150–160 showed the best correlation (R2 = 0.94 ± 0.03, intercept = 0.07 ± 0.02, slope = 0.94 ± 0.01). SUVR reproducibility between test-retest sessions was also excellent for each time-interval. These results were valid for pooled regions as well as at regional level. This study confirms the feasibility of static acquisitions to facilitate clinical use of the [18F]F13640 radiopharmaceutical to image functional 5-HT1A receptors. This involves off-camera injection, 10 to 20 mins static acquisition duration, and quantification using SUVR, while improving patient comfort.

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

Positron emission tomography (PET) is a molecular imaging modality that enables in vivo exploration of metabolic processes and especially the pharmacology of neuroreceptors. G protein-coupled receptors (GPCR) play an important role in numerous pathophysiologic disorders of the central nervous system. Thus, they are targets of choice in PET imaging to bring proof concept of change in density in pathological conditions or in pharmacological challenge. At present, most radiotracers are antagonist ligands. In vitro data suggest that properties differ between GPCR agonists and antagonists: antagonists bind to receptors with a single affinity, whereas agonists are characterized by two different affinities: high affinity for receptors that undergo functional coupling to G-proteins, and low affinity for those that are not coupled. In this context, agonist radiotracers may be useful tools to give functional images of GPCRs in the brain, with high sensitivity to neurotransmitter release. Here we review all existing PET radiotracers and their role for understanding the ligand-receptor paradigm of GPCR in comparison with corresponding antagonist radiotracers.

Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact. We explored the glucose metabolism with [ F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [ F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs. No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline. This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.

Rapid-acting antidepressants (RAADs) such as ketamine are currently under development. The aim of this study is to characterize the neural circuits affected by ketamine and NLX-101, a selective 5-HT 1A receptor biased agonist which has shown promising effects, by using [ 18 F]FDG PET imaging in rats that had received chronic administration of corticosterone (CORT), a model of anxiety-depression. In a longitudinal study, regional changes in brain activity were investigated in 24 selected CORT rats. Each animal underwent PET scans in 3 conditions, i.e. with ketamine (10 mg/kg), NLX-101 (0.16 mg/kg) or saline on day 0 and five days later to assess sustained effects. The anxious-depressive phenotype produced by CORT was supported by behavioural and biological observations. Changes in [ 18 F]FDG uptake were determined using voxel-based and region of interest analyses. Metabolic connectivity analysis was also performed to investigate the acute and delayed effects of the treatments. Voxel-based and region-of-interest analyses showed marked hypometabolism in regions implicated in depression, particularly cingulate cortex (−7%) and lateral septum (−9%) as well as the striatum (−10%). Acute effects of NLX-101 and ketamine were observed in the lateral septum, resulting in an increase in brain glucose metabolism (p < 0,05). Interestingly, connectivity analyses also showed effects of NLX-101 in the frontal cortex, the thalamus and amygdala (p < 0.05), suggesting that the two molecules converge on common brain regions. This study is the first to show brain activation patterns of RAADs in a CORT rat model by functional PET imaging. NLX-101 appears to exert antidepressant effects by preferentially activating postsynaptic 5-HT 1A heteroreceptors in primary regions common to ketamine. These results support investigation of cortical 5-HT 1A receptors as a target for new generation biased agonist antidepressants. Highlights [ 18 F]FDG-PET imaging was used in rats which had received chronic corticosterone administration. Corticosterone treated rats exhibited decreased glucose consumption in multiple brain regions. NLX-101, a 5-HT 1A receptor biased agonist, and ketamine modified glucose consumption in cortex and lateral septum. These brain regions may contribute to the RAAD-like properties of the compounds.

This systematic review and meta-analysis aimed to assess the efficacy of NMDA antagonists in ASD (Autism Spectrum Disorder) on the core (communication and social interaction, repetitive behavior) and associated symptoms (irritability) of ASD, as well as their safety. PubMed, CENTRAL, CINHAL, EMBASE, and PsycINFO databases were searched until November 2023. Two authors independently selected the studies and extracted data. Randomized controlled trials assessing the efficacy of NMDA receptor antagonists in participants with ASD aged <18 years were included. The quality of the studies was assessed using the Risk of Bias-2 tool. A random-effect meta-analysis model was used to calculate standardized mean differences (SMD) or odds ratios (OR) using meta package in R. This systematic review included ten studies (588 participants). Most studies did not report scales assessing core symptoms of ASD. Meta-analysis of efficacy on ASD core symptoms included three studies (248 participants). NMDA antagonists were not superior to placebo [SMD = 0.29; CI 95% (-1,94; 1.35); I = 0%]. NMDA antagonists was not superior to placebo concerning response (four studies, 189 participants) [OR = 2.4; CI 95% (0.69; 8.38); I = 35%]. Meta-analysis of efficacy on irritability included three studies (186 participants); NMDA antagonists were not superior to placebo [MD irritability = -1.94; CI 95% (-4.66; 0.77); I = 0%]. Compared with placebo, significantly more participants in the NMDA antagonist group reported at least one adverse event (five studies, 310 participants) [OR = 2.04; CI 95% (1.17; 3.57); I = 0%]. Current evidence does not support the effectiveness of NMDA antagonists in the treatment of ASD symptoms or irritability. Further research is needed due to the limited and low quality data available. PROSPERO CRD42018110399.

Donepezil (DPZ) is a potent acetylcholinesterase inhibitor, largely used worldwide to alleviate cognitive symptoms in Alzheimer’s disease (AD). Beyond the widely described neuronal impact of donepezil, it was recently shown that targeting the proteins involved in astrocyte network organization might potentiate donepezil efficacy profile using behavioral tests in AD rodent models. The present study provides new perspectives, both (i) through the use of pharmaco-fUS, a new non-clinical imaging modality to move forwards drug discovery in AD and (ii) by the profiling of two drugs on brain dynamics, one used in AD – donepezil – and the other in development – donepezil combined with mefloquine as a modulator of astrocyte network in THN201 combination.

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. 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). 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. 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.