ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity

Kinetic analysis of [11C]befloxatone in the human brain, a selective radioligand to image monoamine oxidase A.

International audienceBACKGROUND: [11C]Befloxatone measures the density of the enzyme monoamine oxidase A (MAO-A) in the brain. MAO-A is responsible for the degradation of different neurotransmitters and is implicated in several neurologic and psychiatric illnesses. This study sought to estimate the distribution volume (VT) values of [11C]befloxatone in humans using an arterial input function. METHODS: Seven healthy volunteers were imaged with positron emission tomography (PET) after [11C]befloxatone injection. Kinetic analysis was performed using an arterial input function in association with compartmental modeling and with the Logan plot, multilinear analysis (MA1), and standard spectral analysis (SA) at both the regional and voxel level. Arterialized venous samples were drawn as an alternative and less invasive input function. RESULTS: An unconstrained two-compartment model reliably quantified VT values in large brain regions. A constrained model did not significantly improve VT identifiability. Similar VT results were obtained using SA; however, the Logan plot and MA1 slightly underestimated VT values (about -10 %). At the voxel level, SA showed a very small bias (+2 %) compared to compartmental modeling, Logan severely underestimated VT values, and voxel-wise images obtained with MA1 were too noisy to be reliably quantified. Arterialized venous blood samples did not provide a satisfactory alternative input function as the Logan-VT regional values were not comparable to those obtained with arterial sampling in all subjects. CONCLUSIONS: Binding of [11C]befloxatone to MAO-A can be quantified using an arterial input function and a two-compartment model or, in parametric images, with SA

Imaging Characteristics of Choroid Plexuses in Presymptomatic Multiple Sclerosis. A Retrospective Study

Background and Objectives Recent imaging studies have suggested a possible involvement of the choroid plexus (CP) in multiple sclerosis (MS). Here, we investigated whether CP changes are already detectable at the earliest stage of MS, preceding symptom onset. Methods This study is a retrospective analysis of 27 patients with presymptomatic MS, 97 patients with clinically definite MS (CDMS), and 53 healthy controls (HCs) who underwent a cross-sectional 3T-MRI acquisition; of which, 22 MS, 19 HCs, and 1 presymptomatic MS (evaluated 8 months before conversion to CDMS) also underwent translocator protein (TSPO) F-18-DPA-714 PET and were included in the analysis. CPs were manually segmented on 3D T1-weighted images for volumetric analysis. CP F-18-DPA-714 uptake, reflecting inflammation, was calculated as the average standardized uptake value (SUV). Multivariable regressions adjusted for age, sex, and ventricular and brain volume were fitted to test CP volume differences between presymptomatic patients and MS or HCs. For the presymptomatic case who also had F-18-DPA-714 PET, CP SUV differences with MS and HCs were assessed through Crawford-Howell tests. To provide further insight into the interpretation of F-18-DPA-714-PET uptake at the CP level, a postmortem analysis of CPs in MS vs HCs was performed to characterize the cellular localization of TSPO expression. Results Compared with HCs, patients with presymptomatic MS had 32% larger CPs (beta = 0.38, p = 0.001), which were not dissimilar to MS CPs (p = 0.69). Moreover, in the baseline scan of the presymptomatic case who later on developed MS, TSPO PET showed 33% greater CP inflammation vs HCs (p = 0.04), although no differences in F-18-DPA-714 uptake were found in parenchymal regions vs controls. CP postmortem analysis identified a population of CD163(+) mononuclear phagocytes expressing TSPO in MS, possibly contributing to the increased F-18-DPA-714 uptake. Discussion We identified an imaging signature in CPs at the presymptomatic MS stage using MRI; in addition, we found an increased CP inflammation with PET in a single presymptomatic patient. These findings suggest a role of CP imaging as an early biomarker and argue for the involvement of the blood-CSF barrier dysfunction in disease development

A blood-free modeling approach for the quantification of the blood-to-brain tracer exchange in TSPO PET imaging

INTRODUCTION: Recent evidence suggests the blood-to-brain influx rate ( K 1 ) in TSPO PET imaging as a promising biomarker of blood-brain barrier ( BBB) permeability alterations commonly associated with peripheral inflammation and heightened immune activity in the brain. However, standard compartmental modeling quantification is limited by the requirement of invasive and laborious procedures for extracting an arterial blood input function. In this study, we validate a simplified blood-free methodologic framework for K 1 estimation by fitting the early phase tracer dynamics using a single irreversible compartment model and an image-derived input function ( 1T1K-IDIF). METHODS: The method is tested on a multi-site dataset containing 177 PET studies from two TSPO tracers ([ 11C]PBR28 and [ 18F]DPA714). Firstly, 1T1K-IDIF K 1 estimates were compared in terms of both bias and correlation with standard kinetic methodology. Then, the method was tested on an independent sample of [ 11C]PBR28 scans before and after inflammatory interferon- α challenge, and on test-retest dataset of [ 18F]DPA714 scans. RESULTS: Comparison with standard kinetic methodology showed good-to-excellent intra-subject correlation for regional 1T1K-IDIF-K 1 ( ρ intra  = 0.93 ± 0.08), although the bias was variable depending on IDIF ability to approximate blood input functions (0.03-0.39 mL/cm 3/min). 1T1K-IDIF-K 1 unveiled a significant reduction of BBB permeability after inflammatory interferon- α challenge, replicating results from standard quantification. High intra-subject correlation ( ρ  = 0.97 ± 0.01) was reported between K 1 estimates of test and retest scans. DISCUSSION: This evidence supports 1T1K-IDIF as blood-free alternative to assess TSPO tracers' unidirectional blood brain clearance. K 1 investigation could complement more traditional measures in TSPO studies, and even allow further mechanistic insight in the interpretation of TSPO signal. </p

Comparison of Pittsburgh compound B and florbetapir in cross-sectional and longitudinal studies.

IntroductionQuantitative in vivo measurement of brain amyloid burden is important for both research and clinical purposes. However, the existence of multiple imaging tracers presents challenges to the interpretation of such measurements. This study presents a direct comparison of Pittsburgh compound B-based and florbetapir-based amyloid imaging in the same participants from two independent cohorts using a crossover design.MethodsPittsburgh compound B and florbetapir amyloid PET imaging data from three different cohorts were analyzed using previously established pipelines to obtain global amyloid burden measurements. These measurements were converted to the Centiloid scale to allow fair comparison between the two tracers. The mean and inter-individual variability of the two tracers were compared using multivariate linear models both cross-sectionally and longitudinally.ResultsGlobal amyloid burden measured using the two tracers were strongly correlated in both cohorts. However, higher variability was observed when florbetapir was used as the imaging tracer. The variability may be partially caused by white matter signal as partial volume correction reduces the variability and improves the correlations between the two tracers. Amyloid burden measured using both tracers was found to be in association with clinical and psychometric measurements. Longitudinal comparison of the two tracers was also performed in similar but separate cohorts whose baseline amyloid load was considered elevated (i.e., amyloid positive). No significant difference was detected in the average annualized rate of change measurements made with these two tracers.DiscussionAlthough the amyloid burden measurements were quite similar using these two tracers as expected, difference was observable even after conversion into the Centiloid scale. Further investigation is warranted to identify optimal strategies to harmonize amyloid imaging data acquired using different tracers

European Ultrahigh-Field Imaging Network for Neurodegenerative Diseases (EUFIND).

INTRODUCTION: The goal of European Ultrahigh-Field Imaging Network in Neurodegenerative Diseases (EUFIND) is to identify opportunities and challenges of 7 Tesla (7T) MRI for clinical and research applications in neurodegeneration. EUFIND comprises 22 European and one US site, including over 50 MRI and dementia experts as well as neuroscientists. METHODS: EUFIND combined consensus workshops and data sharing for multisite analysis, focusing on 7 core topics: clinical applications/clinical research, highest resolution anatomy, functional imaging, vascular systems/vascular pathology, iron mapping and neuropathology detection, spectroscopy, and quality assurance. Across these topics, EUFIND considered standard operating procedures, safety, and multivendor harmonization. RESULTS: The clinical and research opportunities and challenges of 7T MRI in each subtopic are set out as a roadmap. Specific MRI sequences for each subtopic were implemented in a pilot study presented in this report. Results show that a large multisite 7T imaging network with highly advanced and harmonized imaging sequences is feasible and may enable future multicentre ultrahigh-field MRI studies and clinical trials. DISCUSSION: The EUFIND network can be a major driver for advancing clinical neuroimaging research using 7T and for identifying use-cases for clinical applications in neurodegeneration

Estimation de la fonction d'entrée en tomographie par émission de positons dynamique (application au fluorodesoxyglucose)

La tomographie par émission de positons (TEP) est une méthode d imagerie fonctionnelle, utilisée en particulier lors du développement de nouveaux médicaments et pour imager les tumeurs. En TEP, l estimation de la concentration plasmatique artérielle d activité du traceur non métabolisé (nommée fonction d entrée ) est nécessaire pour l extraction des paramètres pharmacocinétiques. Ceux-ci permettent de quanti er le comportement du traceur dans les tissus, ou plus précisément le traitement du traceur par les tissus. Cette thèse constitue une contribution à l étude de la fonction d entrée, par l élaboration d une méthode d estimation de la fonction d entrée peu invasive à partir des images TEP et de prélèvements veineux. L exemple du traceur FDG (analogue du glucose) dans le cerveau humain a été choisi. La méthode proposée repose sur la modélisation compartimentale de l organisme : elle déconvolue le modèle à trois compartiments utilisé pour le FDG. L originalité de la méthode repose sur trois points : l utilisation d un grand nombre de régions d intérêt ; l utilisation d un grand nombre de jeux de trois régions d intérêt différentes; une estimation itérative. Pour la validation de la méthode, un soin particulier a été porté à la simulation d images TEP (simulation d acquisition, reconstruction, corrections) de plus en plus réalistes, depuis une image simple simulée avec un simulateur analytique jusqu à une image la plus proche possible de la réalité, simulée avec simulateur Monte-Carlo. Une chaîne de pré-traitement (segmentation des IRM associés, recalage entre images TEP et IRM et correction de l effet de volume partiel par une variante de la méthode de Rousset) a ensuite été appliquée à ces images a n d extraire les cinétiques des régions d intérêt, données d entrée de la méthode d estimation de la fonction d entrée. L évaluation de la méthode sur di érentes données, simulées et réelles, est présentée, ainsi que l étude de la sensibilité de la méthode à différents facteurs tels que les erreurs de segmentation, de recalage, de mesure de l activité des prélèvements sanguins.Positron Emission Tomography (PET) is a method of functional imaging, used in particular for drug development and tumor imaging. In PET, the estimation of the arterial plasmatic activity concentration of the non-metabolized compound (the "input function") is necessary for the extraction of the pharmacokinetic parameters. These parameters enable the quanti cation of the compound dynamics in the tissues. This PhD thesis contributes to the study of the input function by the development of a minimally invasive method to estimate the input function. This method uses the PET image and a few blood samples. In this work, the example of the FDG tracer is chosen. The proposed method relies on compartmental modeling: it deconvoluates the three-compartment-model. The originality of the method consists in using a large number of regions of interest (ROIs), a large number of sets of three ROIs, and an iterative process. To validate the method, simulations of PET images of increasing complexity have been performed, from a simple image simulated with an analytic simulator to a complex image simulated with a Monte-Carlo simulator. After simulation of the acquisition, reconstruction and corrections, the images were segmented (through segmentation of an IRM image and registration between PET and IRM images) and corrected for partial volume effect by a variant of Rousset s method, to obtain the kinetics in the ROIs, which are the input data of the estimation method. The evaluation of the method on simulated and real data is presented, as well as a study of the method robustness to different error sources, for example in the segmentation, in the registration or in the activity of the used blood samples.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Comparison between Synb0-DisCo and Fieldmap-based methods to correct for distortion artifacts in diffusion MRI

International audienceDiffusion-weighted images acquired with echo planar imaging (EPI) are sensitive to static magnetic field inhomogeneities that can cause distortion artifacts in the phase encoding direction. These artifacts are detrimental for the analyses and several methods have been developed to correct them. Some methods require the acquisition of a dedicated B 0 map like the fieldmap-based method and the state-of-theart "blip-up/blip-down" method. Others do not, like methods using non-rigid registration to a structural image, but they show weaker results. Recently, a method called Synthesized b0 Distortion Correction (Synb0-DisCo) that uses deep learning to perform corrections without additional data (Schilling et al. 2020) has been developed. This study evaluates the Synb0-DisCo algorithm against the other mentioned methods. We performed comparisons on the displacement fields, the $b$ = 0 (diffusion-unweighted) images, and between the $b$ = 0 images and the T1-weighted images; using monocentric data from 50 healthy subjects. We found that, in this context, the methods using fieldmaps outperform the Synb0-DisCo method in most respects

High density of nicotinic receptors in the cingulo-insular network

The nicotinic system plays an important role in ordinary cognition, particularly in attention. The main nicotinic receptor in the human brain is the heteromeric α4β2 neuronal nicotinic acetylcholine receptor (nAChR), which is distributed throughout the brain, with an especially high density in the thalamus and brainstem. Despite the important role of α4β2 nAChRs in various physiological functions and pathological conditions, their distribution in the human cortex remains poorly characterized. We assessed the in vivo distribution of α4β2 nAChRs in the human cortex in a group of seven non-smoking healthy subjects, using 2-[(18)F]F-A-85380 PET and a volume-of-interest-based analysis. We showed that cortical nAChR density was highest in the insular and anterior cingulate cortices. In functional magnetic resonance imaging studies, these two cortical regions and the thalamus have been shown to be highly correlated during the resting state and various tasks. Here, we also directly assessed nAChR density in this cingulo-insular network as defined in an independent dataset using resting-state functional connectivity, and compared it to other control-related networks, to the default mode network as well as to sensory and motor networks. Receptor density was significantly higher in the cingulo-insular network. This network has been suggested to maintain a variety of foundational capacities fundamental to cognitive function. The demonstration of a high nAChR density in the insular and anterior cingulate cortices reflects a particular neurochemical organization of the cingulo-insular network, and suggests an important role of the nicotinic receptors in its functions