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Autism spectrum disorder (ASD) is a neurodevelopmental disorder whose pathophysiological mechanisms are still unclear. Hypotheses suggest a role for glutamate dysfunctions in ASD development, but clinical studies investigating brain and peripheral glutamate levels showed heterogenous results leading to hypo- and hyper-glutamatergic hypotheses of ASD. Recently, studies proposed the implication of elevated mGluR5 densities in brain areas in the pathophysiology of ASD. Thus, our objective was to characterize glutamate dysfunctions in adult subjects with ASD by quantifying (1) glutamate levels in the cingulate cortex and periphery using proton magnetic resonance spectroscopy and metabolomics, and (2) mGluR5 brain density in this population and in a validated animal model of ASD (prenatal exposure to valproate) at developmental stages corresponding to childhood and adolescence in humans using positron emission tomography. No modifications in cingulate Glu levels were observed between individuals with ASD and controls further supporting the difficulty to evaluate modifications in excitatory transmission using spectroscopy in this population, and the complexity of its glutamate-related changes. Our imaging results showed an overall increased density in mGluR5 in adults with ASD, that was only observed mostly subcortically in adolescent male rats prenatally exposed to valproic acid, and not detected in the stage corresponding to childhood in the same animals. This suggest that clinical changes in mGluR5 density could reflect the adaptation of the glutamatergic dysfunctions occurring earlier rather than being key to the pathophysiology of ASD.

Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.

The first access to N-1, N-4 disubstituted pyrrolo[2,3-d][1,2,3]triazoles is reported. The series were generated using a “one-pot” MCR, leading to a single regioisomer of the attempted heteroaromatic skeleton in good yields. Next, the functionalization of C-5 and C-6 positions was investigated. (Het)aryl groups were introduced at the C-5 and C-6 positions of the pyrrolo[2,3-d][1,2,3]triazoles using regioselective electrophilic brominations followed by Suzuki–Miyaura cross coupling reactions. Palladium-catalyzed cross-coupling conditions were optimized and a representative library of various boronic acids was employed to establish the scope and limitations of the method.

Age-related neurodegenerative diseases have in common the occurrence of cognitive impairment, a highly incapacitating process that involves the cholinergic neurotransmission system. The vesicular acetylcholine transporter (VAChT) positron emission tomography (PET) tracer [

BACKGROUND To evaluate in healthy human brain the distribution, uptake, and kinetics of [18F]LBT-999, a PET ligand targeting the dopamine transporter, to assess its ability to explore dopaminergic innervation, using a shorter protocol, more convenient for patients than currently with [123I]ioflupane. METHODS After intravenous injection of [18F]LBT-999, 8 healthy subjects (53-80y) underwent a dynamic PET-scan. Venous samples were concomitantly obtained for metabolites analysis. Time activity curves (TACs) were generated for several ROIs (caudate, putamen, occipital cortex, substantia nigra and cerebellum). Cerebellum was used as reference region to calculate binding potentials (BPND). RESULTS No adverse events or detectable pharmacological effects were reported. [18F]LBT-999 PET revealed a good cerebral distribution, with an intense and symmetric uptake in both putamen and caudate (BPND of 6.75±1.17 and 6.30±1.17, respectively), without other brain abnormal tracer accumulation. Regional TACs showed a plateau from the maximal uptake, 20min pi, to the end of the acquisition for both caudate and putamen, whereas uptake in substantia nigra decreased progressively. A faster clearance and lowest BPND values were observed in both cortex and cerebellum. Ratios to the cerebellum exhibit value of about 3 in substantia nigra, close to 10 for both caudate and putamen, and remained around the value of 1 in cortex. The parent fraction of [18F]LBT-999 in plasma was 80%, 60% and 45% at 15, 30 and 45 min pi, respectively. CONCLUSIONS These findings support the usefulness of [18F]LBT-999 for a quantitative clinical evaluation of presynaptic dopaminergic innervation.

We synthesized 5-[18 F]-fluoro-1H-indol-2-yl)(4-methyl-1-piperazinyl)methanone ([18 F]5) via a Suzuki approach starting from a protected pinacol borane precursor followed by acidic hydrolysis of the t-Boc protecting group. The non-optimized radiochemical yield was 5.7 ± 1.35%, radiochemical purity was over 99%, and molar activity was 100.7 ± 34.5 GBq/μmol (n = 3). [18 F]5 was stable in rat plasma for at least 4 h and was evaluated by μPET imaging and biodistribution using a unilateral quinolinic acid rat model of neuroinflammation. The time-activity curve showed that [18 F]5 entered the brain immediately after intravenous injection and then left it progressively with a very low level reached from 30 min after injection. The biodistribution study showed no difference in the accumulation of [18 F]5 between the lesioned and intact side of the brain and between control rats and animals pretreated with a saturating dose of JNJ-7777120 as a specific H4R antagonist. Hence, despite its in vitro nanomolar affinity for H4R, and its ability to cross the blood-brain barrier in rats, [18 F]5 does not appear suitable to image in vivo the receptor by PET.

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Introduction: Conventional metabolite analyses often require manual sample preparation, generating variability of measurements. This study describes a new method to quantify radiometabolites in blood, combining ultra high performance liquid chromatography (UHPLC) and turbulent flow chromatography, an alternative fully automated process allowing analyte’s extraction. Methods: A new radiotracer for dopamine transporter imaging, namely LBT-999, was used to demonstrate the method’s robustness. Matrix effect, Turboflow column loading, linearity, specificity and precision were evaluated with in vitro samples of LBT-999 in human plasma. Radiodetector sensitivity and preliminary evaluation were respectively determined by analysis of calibrated samples of [18F]LBT-999 and blood samples from 4 healthy subjects injected with [18F]LBT-999, withdrawn at 5, 15, 30 and 45 min pi. Results: With three sequential loadings (3 × 100 μL) of the Turboflow column, mean coefficients of variation were 1%, below 2%, 2% and 30.9% for matrix effect, specificity, repeatability and intermediate precision, respectively. Correlation coefficients for linearity were superior to 0.97. Limits of detection and quantification of the radiodetector were fixed at 3 and 9 c/s. Retention times for [18F]LBT-999 and the two radiometabolites detected by radio-UHPLC were 6.5, 4.8 and 9.6 min. Forty-five min after the injection, parent fraction was still predominant with 57.8% ± 25% of the total radioactivity. Conclusions: An innovative approach, allying UHPLC and Turboflow column, was developed and its sensitivity, linearity, specificity and repeatability validated. Preliminary results of the clinical trial are in accordance with literature data, demonstrating its efficiency in radiometabolites quantification.

A series of novel derivatives exhibiting high affinity and selectivity towards the COX-2 enzyme in the (aza) indazole series was developed. A short synthetic route involving a bromination/arylation sequence under microwave irradiation and direct C–H activation were established in the indazole and azaindazole series respectively. In vitro assays were conducted and structural modifications were carried out on these scaffolds to furnish compound 16 which exhibited effective COX-2 inhibitory activity, with IC50 values of 0.409 µM and an excellent selectivity versus COX-1. Radiolabeling of this most potent derivative [18F]16 was achieved after boron ester release and the tracer was evaluated in vivo in a rat model of neuroinflammation. All chemistry, radiochemistry and biological experimental data are discussed., Graphical Abstract

e12557 Background: Triple-negative breast cancer (TNBC) tends to exhibit aggressive behavior lacking from targeted therapies. Tumor-associated-macrophages (TAMs as M2 and M1 macrophages) are interest targets in TNBC to approach the tumor patient immunity. The mitochondrial translocator protein (TSPO), a sensitive marker for macrophages, could be interesting for TNBC micro-environment stratification. We performed a multicenter imaging pilot study (NCT04320030) using non-invasive [18F]DPA-714 (DPA), a TSPO PET radioligand, aiming at assessing immunity to define the immunotherapy possibilities in TNBC patients. Methods: All patients underwent TSPO genotyping (LAB: Low Affinity Binder, MAB: Mixed and HAB: High), [18F]FDG (FDG) and DPA PET-CT, macrophages immunochemistry and in vitro TSPO autoradiography using both tritiated PK11195 (PK) and DPA. Thorax PET-CT was acquired just after injection (DPA1) to 30 min, then from 45 min (DPA2) to 60 min, followed by a whole body PET-CT. Groups of interest (Macrophages immunochemistry and Genotype) were compared using Kruskal-Wallis test. Correlation between continuous parameters were determined using Spearman’s Rho. Results: A total of 13 TNBC patients were included. No adverse events occurred after DPA injection. For TSPO genotyping, 2/13 (15.5%) patients were LAB, 6/13 (46%) MAB and 5/13 (38.5%) HAB. All of them showed FDG and DPA uptake regardless of the patient's genotype without significant difference between the 3 groups. The DPA kinetics showed a tracer accumulation between DPA1 and DPA2, whatever patient genotypes, observed on SUVmax (p = 0.0015), SUVmean (p = 0.0015) and TL-DPA (p = 0.0024). A correlation between FDG and DPA1 either DPA2 tumor volume was shown, respectively (p = 0.0252 and 0.0067) as well as between the TLG (FDG) and the TL-DPA1 (p = 0.0346) regardless of the patient's genotype. Macrophages immunochemistry showed a tendency difference for M2 percentage (p = 0.09) between the 3 genotypes groups. In vitro binding ratio (PK/DPA), measured for both radioligands, on adjacent tumor slices, was 1.77 (1.35-2.21). A difference in this binding ratio was observed between MAB and HAB (Mean 1.68±0.36) compared to LAB 3.04±0.23 (p = 0.0367), suggesting that DPA binding is sensitive to TSPO genotype, unlike PK binding. Conclusions: Despite the limited population, all TNBC tumor patients were DPA positive with an accumulation over time. The total glycolysis and total DPA uptake in the tumor were correlated, which may link tumor aggressiveness and DPA uptake. These data were confirmed by a better sensitivity for HAB and MAB vs LAB. DPA seemed to be a promising tracer to explore non-invasively TNBC patient’s immunity. Clinical trial information: NCT04320030.

This guideline on molar activity (Am) and specific activity (As) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of Am and As, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of Am and As in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common Am pitfalls and remedies are described. Finally, some aspects of Am in relation the emergence of a new generation of highly sensitive PET scanners will be discussed.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aβ) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.

Purpose Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" F-florbetapir scans. Then, we compare the quantification and distribution of F-florbetapir uptake with those of typical, predominantly amnestic AD patients. Methods We conducted a PET study with F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic-variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. Results Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were F-florbetapir positive. A significantly higher F-florbetapir uptake was observed in PPA F-florbetapir-positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. Conclusions These results suggest that F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome.

Microglia are potential targets for therapeutic intervention in neurological and neurodegenerative diseases affecting the central nervous system. In order to assess the efficacy of therapies aimed to reduce the tissue damaging activities of microglia and/or to promote the protective potential of these cells, suitable pre-clinical and clinical tools for the in vivo analysis of microglia activities and dynamics are required. The aim of this work was to identify new translational markers of the anti-inflammatory / protective state of microglia for the development of novel PET tracers. Methods: New translational markers of the anti-inflammatory/protective activation state of microglia were selected by bioinformatic approaches and were in vitro and ex vivo validated by qPCR and immunohistochemistry in rodent and human samples. Once a viable marker was identified, a novel PET tracer was developed. This tracer was subsequently confirmed by autoradiography experiments in murine and human brain tissues. Results: Here we provide evidence that P2RY12 expression increases in murine and human microglia following exposure to anti-inflammatory stimuli, and that its expression is modulated in the reparative phase of experimental and clinical stroke. We then synthesized a novel carbon-11 labeled tracer targeting P2RY12, showing increased binding in brain sections of mice treated with IL4, and low binding to brain sections of a murine stroke model and of a stroke patient. Conclusion: This study provides new translational targets for PET tracers for the anti-inflammatory/protective activation state of microglia and shows the potential of a rationale-based approach. It therefore paves the way for the development of novel non-invasive methodologies aimed to monitor the success of therapeutic approaches in various neurological diseases.

Les depots extracellulaires de plaques seniles principalement constituees de proteine Aβ et les lesions intracellulaires ou degenerescences neurofibrillaires (DFN) constituees de proteine tau hyperphosphorylee sont caracteristiques de maladie d’Alzheimer (MA). Ces lesions caracteristiques se developpent bien en amont des premiers symptomes. Les lesions de DNF semblent correlees a la symptomatologie clinique et permettent de classer la maladie d’Alzheimer en stades neuropathologiques. Ces dernieres annees, des radioligands specifiques de la proteine tau ont ete developpes permettant de realiser une imagerie in vivo de la distribution et de la densite des lesions de DNF. Dans cette etude, nous avons evalue le profil de fixation (densite et distribution cerebrale) des agregats tau a l’aide de la TEP au [18F]-AV-1451 ([18F]-T807 ou flortaucipir ou Tauvid®) chez un groupe de 9 patients avec diagnostic clinique de MA ou de pathologie neurodegenerative apparentee mais de profil evolutif tres variable (MMS ente 15 et 25). Tous les sujets ont egalement beneficie d’une TEP au [18F]-FDG afin d’evaluer leur activite metabolique neuronale. Pour chaque sujet, l’intensite de fixation du [18F]-T807 et le degre d’hypometabolisme ont ete quantifies visuellement en 5 niveaux pour chaque region corticale predefinie. Quatre sujets avaient un tableau hypometabolique confortant leur diagnostic et qui, par ailleurs, concordait avec la distribution de la DNF. Pour 4 autres sujets, 2 ne presentaient ni un hypometabolisme ni un tableau de DFN significatifs et les 2 autres presentaient un hypometabolisme predominant dans le cortex fronto-temporal sans lesion significative de DNF. Le 9eme sujet presentait un hypometabolisme cortical diffus avec peu de lesions de DNF. Malgre un nombre tres limite de sujets, ces resultats semblent confirmer le lien etroit entre la presence de lesions de DNF visibles en imagerie TEP tau et le profil clinique et metabolique dans la MA et pathologies apparentees.

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [ 18 F] radiolabelled derivatives. It can be expected from our results that some of these compounds will be suitable for further developments and will have effects on cognitive disorders.

The nicotinic acetylcholine alpha-7 receptors (α7R) are involved in a number of neuropsychiatric and neurodegenerative brain disorders such as Parkinson's disease (PD). However, their specific pathophysiologic roles are still unclear. In this context, we studied the evolution of these receptors in vivo by positron emission tomography (PET) imaging using the recently developed tracer 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[PET imaging of α7R was performed at 3, 7, and 14 days following a partial striatal unilateral lesion with 6-hydroxydopamine in adult rats. After the last imaging experiments, the status of nigro-striatal dopamine neurons as well as different markers of neuroinflammation was evaluated on brain sections by autoradiographic and immunofluorescent experiments.We showed an early and transitory rise in α7R expression in the lesioned striatum and substantia nigra, followed by over-expression of several gliosis activation markers in these regions of interest.These findings support a longitudinally follow-up of α7R in animal models of PD and highlight the requirement to use a potential neuroprotective approach through α7R ligands at the early stages of PD.

In this paper we describe the design and synthesis of bis(Het)Aryl-1,2,3-triazole quinuclidine α7R ligands using an efficient three-step sequence including a Suzuki-Miyaura cross coupling reaction with commercially available and home-made boron derivatives. The exploration of SAR required the preparation of uncommon boron derivatives. Forty final drugs were tested for their ability to bind the target and nine of them exhibited Ki values below nanomolar concentrations. The best scores were always obtained when the 5-phenyl-2-thiophenyl core was attached to the triazole. The selectivity of these compounds towards the nicotinic α4β2 and serotoninergic 5HT3 receptors was assessed and their brain penetration was quantified by the preparation and in vivo evaluation of two [

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons constituting the nigrostriatal pathway. Neuroinflammation, related to microglial activation, plays an important role in this process. Exploration of animal models of PD using neuroimaging modalities allows to better understand the pathophysiology of the disease. Here, we fully explored a moderate lesion model in the rat in which 6-hydroxydopamine was unilaterally delivered in three sites along the striatum. The degenerative process was assessed through in vivo Positron Emission Tomography (PET) imaging and in vitro autoradiographic quantitation of the striatal dopamine transporter (DAT) and immunostaining of tyrosine hydroxylase (TH). The microglial activation was studied through in vitro autoradiographic quantitation of the 18 kDa translocator protein (TSPO) in the striatum and CD11b staining in the SN. In addition, a targeted metabolomics exploration was performed in both these structures using mass spectrometry coupled to HPLC. Our results showed a reproducible decrease in the striatal DAT density associated with a reduction in the number of TH-positive cells in the SN and striatum, reflecting a robust moderate degeneration of nigrostriatal DA neurons. In addition, we observed strong microglia activation in both the striatum and SN ipsilateral to the lesion, highlighting that this moderate degeneration of DA neurons was associated with a marked neuroinflammation. Our metabolomics studies revealed alterations of specific metabolites and metabolic pathways such as carnitine, arginine/proline, and histidine metabolisms. These results bring new insights in the PD mechanism knowledge and new potential targets for future therapeutic strategies.

This guideline summarizes the current view of the European Association of Nuclear Medicine Drug Development Committee. The purpose of this guideline is to guarantee a high standard of PET studies that are aimed at measuring target occupancy in the brain within the framework of development programs of drugs that act within the central nervous system (CNS drugs). This guideline is intended to present information specifically adapted to European practice. The information provided should be applied within the context of local conditions and regulations.

Highly substituted pyrido[4,3-b]indole derivatives were synthesized through a straightforward one-pot silver-catalyzed process involving 2-alkynylindole-3-carbaldehyde oximes. The tandem cyclization/nucleophilic addition sequence was optimized and applied to a wide range of nucleophiles, which reacted regioselectively at the pyrido[4,3-b]indole C4 position. The scope and limitations of the methodology were evaluated and the final compounds were obtained in fair to very good yields. This versatile method proved to be compatible with various chemical functionalities or (hetero)cycles.

Recently, accumulating evidence has revealed that neuroinflammation appears to be the cornerstone of many neurological diseases including stroke, multiple sclerosis, Alzheimer's disease or Parkinson's disease. Neuroinflammation causes neuronal damages by activation of numerous cells and molecular mediators in diseases involving the inflammatory process. In this article, we focus on noninvasive molecular imaging of radioligands that target inflammatory cells and molecules involved in neuroinflammation. PET is in fact one of the most promising imaging techniques to visualize and quantify neuroinflammation in vivo. We have also summarized the potential neuroinflammation imaging targets and corresponding PET radioligands.

An efficient and convenient method was developed for the formation of S-substituted thiotriazoles through an unprecedented organometallic addition and subsequent ring-opening sequence of 3-substituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole. The method is applicable to a wide range of substrates containing different functional groups and furnishes excellent yields of the corresponding N-unsubstituted 3- or 5-alkyl, aryl, alkynyl and alkenyl sulfanyl-1,2,4-triazole products.

article i nfo Introduction: We examined whether ( 18 F)LBT-999 ((E)-N-(4-fluorobut-2-enyl)2β-carbomethoxy-3β-(4'- tolyl)nortropane) is an efficient positron emission tomography (PET) tracer for the quantification of the dopamine transporter (DAT) in the healthy rat brain. Methods: PET studies were performed using several experimental designs, i.e. test-retest, co-injection with different doses of unlabelled LBT, displacement with GBR12909 and pre-injection of amphetamine. Results: The uptake of ( 18 F)LBT-999 confirmed its specific binding to the DAT. The non-displaceable uptake (BPND) in the striatum, between 5.37 and 4.39, was highly reproducible and reliable, and was decreased by 90% by acute injection of GBR12909. In the substantia nigra/ventral tegmental area (SN/VTA), the variability was higher and the reliability was lower. Pre-injection of amphetamine induced decrease of ( 18 F)LBT-999

Objectif Le transporteur neuronal de la dopamine (DAT) est responsable de la recapture de la dopamine de l’espace synaptique vers les fibres presynaptiques. Selon plusieurs etudes, les symptomes cliniques de la maladie de Parkinson (MP) se manifestent quand la perte de terminaisons dopaminergiques pre-synaptiques atteint deja entre 40 et 50 %. Il est ainsi d’un grand interet de distinguer, a un stade initial, differentes entites syndromiques avec atteinte effective du systeme dopaminergique nigrostrie de celles sans atteinte comme c’est le cas du tremblement essentiel ou du syndrome extrapyramidal iatrogenique. Actuellement, le DaTSCAN® est le seul radiotraceur avec AMM permettant de visualiser et d’etudier in vivo la fonction dopaminergique pre-synaptique en TEMP. Dans cette etude, nous avons valide in vivo chez l’homme un traceur du DAT marque au fluor 18, le LBT-999. Sujets et methodes Huit temoins et 6 malades atteints de MP (Hoehn et Yahr : I–II) ont ete soumis a une acquisition TEP en list-mode pendant 90 minutes suite a l’injection de 3,6MBq/kg de 18F-LBT-999. Pour chaque sujet, en utilisant leurs images IRM, des regions d’interet sur les noyaux caudes (Cd), les putamens (Put) et le cervelet ont ete definies. Des binding potentiel (BP) et des ratios (en utilisant des images de 10 min) ont ete calcules, avec le cervelet comme region de reference. Resultats Aucun sujet n’a repertorie des effets lies a l’administration du radiopharmaceutique. Les valeurs de BP et de ratio sont inferieures (p Conclusions Nos resultats montrent que le 18F-LBT-999 permet l’evaluation de l’atteinte dopaminergique striatale pre-synaptique, en utilisant une analyse simplifiee avec des ratios et une image TEP de 10 min.

BACKGROUND Positron emission tomography (PET) imaging of brain amyloid (Aβ) and neurofibrillary tangle (NFT) load is a candidate biomarker of Alzheimer's disease (AD). OBJECTIVES To compare brain Aβ and NFT load and glucose metabolism in advanced elderly (70 years and older) patients with AD and healthy controls (HCs) by PET with [18F]FDDNP and [18F]FDG. METHODS Seven AD patients (mean ± SD age 79.3 ± 3.6 y, Mini-Mental State Examination (MMSE) score 22.1 ± 2.5) and eight HCs (mean age ± SD, 75.7 ± 3.9 y; MMSE score 29.0 ± 1.2) underwent PET with [18F]FDDNP and [18F]FDG. RESULTS Global [18F]FDDNP uptake was significantly higher (p < 0.05) in AD patients (1.15 ± 0.04) than in HCs (1.10 ± 0.06), while global brain metabolism was lower in AD patients than in HCs (AD patients 0.96 ± 0.09; HCs 1.13 ± 0.11; p < 0.05). In HCs, brain glucose metabolism was correlated with age for both the global [18F]FDG SUVr and in the parietal and posterior cingulate regions, while no correlation was found between age and [18F]FDDNP uptake. In AD patients, global [18F]FDDNP uptake and uptake in the frontal and anterior cingulate regions of interest were correlated with MMSE score, while no correlation was observed with brain glucose metabolism. CONCLUSION Imaging Aβ load and NFT with [18F]FDDNP can distinguish AD patients from HCs in an advanced elderly population. It seems to be less sensitive than [18F]FDG to the brain changes observed with normal aging, but more sensitive to cognitive decline in advanced elderly AD patients.

Fluoro-de-triazenation of 3,3-diethyl-1-aryltriazenes can be achieved by conventional or under microwave heating in carbon tetrachloride, in the presence of boron trifluoride diethyl etherate without any protic acid to avoid corresponding unwanted byproduct formation.

Resume Objectif Etudier la biodistribution physiologique en TEP/TDM du N,N -diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-α]pyrimidin-3-yl) acetamide marque au fluor 18 ( 18 F-DPA-714) chez l’homme, au niveau du cerveau et du corps entier. Le DPA-714 est un ligand de la proteine translocatrice de 18 kDa (TSPO), proteine surexprimee par la microglie en cas de neuroinflammation. Materiel et methodes Des acquisitions dynamiques TEP/TDM cerebrales ont ete realisees chez six sujets sains, pendant 90 minutes, apres injection intraveineuse de 18 F-DPA-714. La biodistribution cerebrale du 18 F-DPA-714 a ete evaluee visuellement et a l’aide de regions d’interets (ROI), selon le referentiel de la MNI-AAL afin d’obtenir les courbes d’activite/temps pour chaque region cerebrale predefinie. Un des sujets inclus a eu egalement des acquisitions TEP/TDM corps entier une heure apres injection du 18 F-DPA-714, permettant une analyse visuelle et semi-quantitative de la distribution du traceur, par definition de ROI et calcul des SUVs max. Resultats La captation cerebrale maximale du 18 F-DPA-714 a ete visualisee vers 3,5 minutes apres injection, au niveau de la substance grise surtout thalamique. Elle a ete suivie de deux phases d’elimination : une premiere phase rapide (3,5–35 minutes), puis une phase plus lente jusqu’en fin d’enregistrement. La captation du 18 F-DPA-714 a ete globalement homogene au sein des structures cerebrales analysees. Les images corps entier ont montre une activite importante au niveau de la vesicule biliaire, du rachis et des glandes salivaires sous-maxillaires, conformement aux precedentes etudes publiees utilisant d’autres radioligands de la TSPO. Conclusion Cette etude, tres preliminaire, confirme que la biodistribution cerebrale du 18 F-DPA-714 fait de lui un marqueur interessant de la neuroinflammation. Elle permet de proposer un protocole d’acquisition des images TEP. Cependant, il semble maintenant necessaire de mettre en application ces resultats chez des sujets malades.

Introduction The translocator protein 18 kDa (TSPO), although minimally expressed in healthy brain, is up-regulated in pathological conditions, coinciding with microglial activation. It is thereby a suitable in vivo biomarker of neuroinflammation for detection, evaluation and therapeutic monitoring of brain diseases. We aimed to estimate the radiation dosimetry of the positron emission tomography (PET) TSPO radioligand [ 18 F]DPA-714, and we evaluated in healthy volunteers its whole-body uptake and cerebral kinetics. Methods Biodistribution data from mice were used for the prediction of radiation dosimetry. In human studies, a 90-min dynamic PET scan was performed in seven healthy volunteers after injection of [ 18 F]DPA-714 (245±45 MBq). Arterial and venous samples were collected from two subjects, and two additional subjects were submitted to whole-body acquisition. Regions of interest were defined over cerebral structures to obtain mean time–activity curves and to estimate the distribution volume ratios by Logan graphical analysis, and over peripheral organs to obtain standard uptake values. Results The effective dose estimated from biodistribution in mice was 17.2 μSv/MBq. Modeling of regional brain and plasma data showed good in vivo stability of [ 18 F]DPA-714 in humans, with only 20% of blood metabolites 20 min postinjection (p.i.). Maximum cerebral uptake was observed 5 min p.i., followed by two decreasing phases: a rapid washout (5–30 min) followed by a slower phase for the remainder of PET acquisition. Whole-body images demonstrate high activity in the gallbladder, heart, spleen and kidneys. Conclusions This initial study in humans shows that [ 18 F]DPA-714 is a promising PET radioligand with excellent in vivo stability and biodistribution, and acceptable effective dose estimation. Therefore, [ 18 F]DPA-714 could provide a sensitive measure of neuroinflammatory changes in subsequent clinical investigations.

Resume Le projet HIMIMT a pour but de valider le potentiel d’un derive de dextran, mimetique fonctionnel des heparanes sulfates, a cibler les matrices extracellulaires lesees du microenvironnement tumoral. Le concept central est de coupler au mimetique des heparanes un radionucleide afin de visualiser in vivo les zones tumorales par methode scintigraphique. Cet article presente les principaux aspects de la technologie developpee et sa pertinence dans le contexte de la medecine nucleaire. Il resume les approches chimiques envisagees dans le developpement de ce nouvel agent radiopharmaceutique innovant.

Objectifs Le glutamate est le principal neurotransmetteur excitateur dans le systeme nerveux central. Les recepteurs metabotropiques du glutamate (mGluR) sont des recepteurs couples a des proteines G, activant des systemes de seconds messagers intracellulaires, pour moduler la neurotransmission glutamatergique. Le sous-type mGluR5 semble etre un regulateur important du systeme glutamatergique en raison de son implication dans differents mecanismes impliques dans la neurogenese et la maintenance synaptique. Plusieurs equipes ont developpe des radiotraceurs specifiques du ce systeme et plus precisement du mGluR5. Dans ce travail, nous avons verifie la pharmacocinetique cerebrale d’un radioligand TEP du mGluR5, le [18]F-FPEB, chez le volontaire sain et propose un protocole d’acquisition adapte aux populations pathologiques. Materiels et methodes Des acquisitions cerebrales dynamiques TEP/TDM (Philips Ingenuity 64) ont ete realisees chez 10 volontaires hommes (âge moyen ± ET : 31 ± 12 ans), pendant 90 min, apres injection intraveineuse de [18F]-FPEB (257 ± 29 MBq). Afin d’obtenir des courbes activite-temps (TAC) et a l’aide du referentiel MNI-AAL, nous avons defini des regions d’interet (ROI) sur differentes structures cerebrales. Resultats Apres un pic maximal obtenu environ 10 min pi, nous avons observe que la fixation du [18F]-FPEB etait maximale au niveau du cortex cingulaire (anterieur et posterieur) et du striatum puis cette fixation decroit ensuite lentement et de facon lineaire jusqu’a la fin de l’acquisition pour l’ensemble des regions cerebrales. Sur les regions connues pour etre moins riches en recepteur mGluR5, et surtout pour le cervelet, la fixation est inferieure aux autres regions. Ceci permet de proposer le cervelet comme region de reference non specifique. Conclusion Pour une acquisition de 90 min, nos resultats sont similaires a ceux obtenus par les equipes americaines qui ont developpe le [18F]-FPEB (Wong et al., 2013, Park et al., 2015, Leurquin-Sterk G et al., 2016). Ils nous permettent egalement de proposer un protocole d’acquisition adapte a des patients avec des durees plus courtes (20 min). Finalement, nos resultats ont confirme l’utilisation du cervelet comme region de reference pour la quantification de la densite de mGluR5. Remerciements Ce travail s’integre dans le programme de l’Agence nationale pour la recherche « Investissements d’Avenir » n°ANR-11-LABX-0018-01), IRON et finance par la Region Centre Val-de-Loire.