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International audience; 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.

Ribonucleoprotein (RNP) granules are dynamic condensates enriched in regulatory RNA binding proteins (RBPs) and RNAs under tight spatiotemporal control. Extensive recent work has investigated the molecular principles underlying RNP granule assembly, unraveling that they form through the self-association of RNP components into dynamic networks of interactions. How endogenous RNP granules respond to external stimuli to regulate RNA fate is still largely unknown. Here, we demonstrate through high-resolution imaging of intact

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.

The aim of this study was to perform in-vitro and in-vivo radiopharmacological characterizations of [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.In all species, autoradiography data revealed high binding levels of [These radiopharmacological data confirm that [

International audience; Background: The 5-HT 6 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 [ 18 F]2FNQ1P, a new specific radiotracer of 5-HT 6 receptors, and to quantify 5-HT 6 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 K D and B max 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 [ 18 F]2FNQ1P specific binding, which parallels 5-HT 6 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-HT 6 receptors in AD and related disorders. [ 18 F]2FNQ1P demonstrated specific binding to 5-HT 6 receptors.

International audience; 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 [11C]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). [18F]BF-227, chemically identical to [11C]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 [18F]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.

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.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.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.(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.

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.Cylindrical LiF thermoluminescence dosimeters were used to measure radiation-related whole-body doses (WBDs) and finger doses of the clinical staff.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.Fortunately, these doses were always lower than the limits reported in the European Directive EURATOM 96/29 05/13/1996 (WBD20 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.