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International audience; The (benzenesulfonyl)difluoromethylsulfanyl (PhSO2 CF2 S) group is a valuable substituent with specific properties which can provide access to new applications of fluoroalkylthiolated compounds. Direct introduction of this moiety can be performed by in an electrophilic manner by using a new shelf-stable reagent, namely a (benzenesulfonyl)difluoromethanesulfenamide. Furthermore, mild magnesium-mediated reduction of the PhSO2 CF2 S group leads to a facile synthesis of difluoromethylthiolated molecules and their deuterated analogs.

International audience

International audience; Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. The 5-HT1A family is the best characterized subtype of the fourteen currently known 5-HT receptors. The 5-HT1A receptor is closely involved in the pathogenesis of anxiety, depression, epilepsy and eating disorders and therefore is an important target for drug therapy. The development in the 1980s of molecules specifically targeting this receptor was followed by the rapid development of corresponding PET neuroimaging. Because this receptor represents a crucial target in neuroscience, a large number of radioligands have been developed by academic and industry centers for visualization and quantification, first in living animals and ultimately in humans. After a brief account of some of the structural and functional characteristics of brain 5-HT1A receptors, this review focuses on the main lines of evolution opened up by preclinical and clinical 5-HT1A PET radiopharmaceuticals, illustrating the potential value of PET for clinical research and drug development.

Présentation orale; International audience; Aim. The 5-HT1A serotonin receptors located in hippocampus are known to be linked to memory processes. PET clinical imaging studies with [18F]MPPF have documented the decrease of 5-HT1A receptor expression in Alzheimer's disease patients, interpreted as neuronal loss. Interestingly, other [18F]MPPF PET studies have reported a specific increase in hippocampal 5-HT1A receptor binding during a pre-dementia stage of Alzheimer's disease (mild cognitive impairment). If this increase in [18F]MPPF binding may be explained by compensatory mechanisms, the pharmacological properties of this PET radiotracer limit its biological interpretation. It is known indeed that [18F]MPPF, which is an antagonist like a majority of available PET receptor radioligands, binds non-specifically to the high-affinity state of 5-HT1A receptors (functional) and to the low-affinity state of these receptors (decoupled from G proteins and non-functional). On the contrary, an agonist binds selectively to the high-affinity state of the receptor which are functional. The Aim of this study is demonstrate that the binding of a 5-HT1A PET agonist provides complementary information to the binding of a 5-HT1A PET antagonist, to improve understanding of the functional impairment of 5-HT1A receptors during Alzheimer's disease. Materials and MJethods. We compared in postmortem human brain sections the specific binding of [18F]F15599, a 5-HT1A PET agonist we developed previously, with the specific binding of [18F]MPPF, a 5-HT1A PET antagonist. Thirty-µm coronal sections were cut across hippocampi of 18 patients at different Braak's stages (from 0 to VI). The days of radiotracers synthesis, the brain slides were incubated in a saline buffer containing 37 kBq/mL of [18F]MPPF or [18F]F15599. Hippocampal subregions were drawn according to a brain atlas and binding quantification was performed with extemporaneous fluorine-18 scales. The specific binding of both radiotracers was determined by addition of 100 nM of serotonin and the agonist binding of [18F]F15599 was revealed by addition of 10 μM of Gpp(NH)p. Results and Conclusion. The autoradiography distribution of both 5-HT1A PET radiotracers varied across hippocampus regions. The highest binding density was found in the pyramidal layer of CA1, followed by the molecular layer of the dentate gyrus. The incubation with 10 μM of Gpp(NH)p, a non-hydrolysable analogue of GTP, reduced significantly [18F]F15599 binding, confirming its specific binding to G-coupled 5-HT1A receptors. [18F]F15599 binding compared to [18F]MPPF binding revealed specific modifications of the density of functional 5-HT1A correlated to the Braak's stages. These results justify an extension of this concept of functional PET imaging in clinical studies.

Présentation orale; International audience; Aims. According to their brain localization, the serotonin 5-HT6 receptors are potent therapeutic targets for psychiatric and neurological diseases, i.e., schizophrenia and Alzheimer's disease. However, the understanding of the serotonin 5-HT6 pharmacology is currently partial and its exploration is limited to animal models, particularly because of the current lack of fluorinated PET 5-HT6 radiopharmaceuticals. In this context, we developed several 5-HT6 fluorinated radioligands and, through a translational approach, evaluated their suitability for PET imaging. Material and Methods. Various quinoline and pyridine-based ligands have been synthesized, inspired by the known 5-HT6 receptor pharmacophore. These non-radioactive fluorinated ligands and their radiolabelling's precursors were obtained from bis-functionalized heteroaromatic core followed by coupling reactions in three steps. Only ligands with the higher in vitro affinities toward 5-HT6 receptors and the lower affinities toward 5-HT2A receptors (a close pharmacophore) were radiolabeled via 18F-nucleophilic aromatic substitution. These potential radiotracers were evaluated by in vitro autoradiography in rat brain. The most interesting radioligands of these were later evaluated by microPET scans on anaesthetized rats, PET scans on anaesthetized cat. Finally, the selected 5-HT6 radioligand was used in postmortem PET autoradiography in brain tissue (control subjects and Alzheimer disease patients). Results and conclusion. Eight molecules were initially synthesised. Three molecules with low in vitro affinity for 5-HT6 receptors were discarded (Ki >10 nM). The chemical and radiochemical purities of the five remaining fluorine radiotracers were > 99%, with a radiochemical yield of 5-45% (EOB) and specific activities in the range of 40-104 GBq/µmole (EOS). Three radiolabelled molecules presented a high in vitro binding in the striatum area rich in 5-HT6 receptors and a dose-dependent displacement after SB258585 addition (a 5-HT6 receptor antagonist). The microPET studies in anesthetized rats showed that one among these three molecules (2FNQ1P) had a good brain penetration and a striatal fixation. PETscans in cats gave additional information about 2FNQ1P pharmacokinetic, showing a good brain penetration and a binding to striatal 5-HT6 receptors. The further evaluations in post-mortem human tissues were in accordance with the known distribution of 5-HT6 receptors in the brain. In conclusion, our study allowed us to select a radiotracer-candidate with suitable characteristics for PET imaging of 5-HT6 receptors, justifying further evaluations and quantitative approach using kinetic models.

Présentation orale; International audience; Objectives: The serotonin 5-HT6 receptors are potent therapeutic targets for psychiatric and neurological diseases, i.e., schizophrenia and Alzheimer's disease. However, the understanding of their pharmacology is currently partial and limited to animal models, particularly because of the lack of fluorinated PET 5-HT6 radiopharmaceuticals. We therefore developed several 5-HT6 radioligands and evaluated their suitability for PET imaging. Methods: Various quinoline and pyridine-based ligands have been synthesized, inspired by the 5-HT6 receptor pharmacophore. The molecules were synthesized by using coupling reactions in 3 steps. Only ligands with high affinities toward 5-HT6 receptors and low affinities toward 5-HT2A receptors (a close pharmacophore) were radiolabeled via 18F-nucleophilic aromatic substitution. These candidates were evaluated by in vitro autoradiography in rat brain. The most interesting radioligands of these were evaluated by in vivo microPET in rat. Results: Eight molecules were initially synthesised and three molecules with low in vitro affinity for 5-HT6 receptors were removed (Ki >10 nM). The chemical and radiochemical purities of the five remaining fluorine radiotracers were > 99%, with a radiochemical yield of 5-45% (EOB) and specific activities in the range of 40-104 GBq/µmole (EOS). Three radiolabelled molecules presented a high in vitro binding in the striatum area rich in 5-HT6 receptors and a dose-dependent displacement by a 5-HT6 receptor antagonist. The microPET studies showed that one among these three molecules had a good brain penetration and a striatal fixation. Conclusions: Our studies allowed to select a radiotracer-candidate with suitable characteristics for PET imaging of 5-HT6 receptors, justifying further evaluations in post-mortem human tissues and the development of chemical analogues.