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Communication Dans Un Congrès Année : 2013

Preclinical evaluation of serotonin 5-HT6 receptor radioligands for PET imaging

Résumé

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.
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Dates et versions

hal-00948359 , version 1 (18-02-2014)

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  • HAL Id : hal-00948359 , version 1

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G. Becker, J. Colomb, T. Billard, L. Zimmer. Preclinical evaluation of serotonin 5-HT6 receptor radioligands for PET imaging. Annual Congress of the European Association of Nuclear Medicine 2013, Oct 2013, Lyon, France. ⟨hal-00948359⟩
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