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Conception, Synthesis and Evaluation of Fluorescent Probes and PET Radioligands for the Oxytocin and Vasopressin Receptors Iuliia Karpenko

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Conception, Synthesis and Evaluation of Fluorescent Probes and PET Radioligands for the Oxytocin and Vasopressin Receptors Iuliia Karpenko Conception, synthesis and evaluation of fluorescent probes and PET radioligands for the oxytocin and vasopressin receptors Iuliia Karpenko To cite this version: Iuliia Karpenko. Conception, synthesis and evaluation of fluorescent probes and PET radioligands for the oxytocin and vasopressin receptors. Medicinal Chemistry. Université de Strasbourg, 2014. English. NNT : 2014STRAF045. tel-01674159v1 HAL Id: tel-01674159 https://tel.archives-ouvertes.fr/tel-01674159v1 Submitted on 2 Jan 2018 (v1), last revised 2 Jan 2018 (v2) HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES CHIMIQUES UMR 7200-Laboratoire d’Innovation Thérapeutique THÈSE présentée par Iuliia KARPENKO soutenue le 16 octobre 2014 pour obtenir le grade de Docteur de l’Université de Strasbourg Discipline / Spécialité : Chimie biologique thérapeutique Conception, synthèse et évaluation de sondes fluorescentes et de radioligands TEP des récepteurs de l’ocytocine et de la vasopressine. THÈSE dirigée par : HIBERT Marcel Professeur, Université de Strasbourg RAPPORTEURS : ACHER Francine Docteur, Université Paris Descartes RENARD Pierre-Yves Professeur, Université de Rouen AUTRES MEMBRES DU JURY : DURROUX Thierry Docteur, Université de Montpellier, INSERM BOLZE Frédéric Docteur, Université de Strasbourg BONNET Dominique Docteur, Université de Strasbourg List of content List of content ............................................................................................................................. 2 List of abbreviations ................................................................................................................... 7 Résumé de thèse ......................................................................................................................... 9 Introduction: the world of GPCRs ........................................................................................... 22 1. G protein – coupled receptors (GPCRs) ........................................................................ 23 1.1. Structural characteristics of GPCRs ....................................................................... 23 1.2. Classification of GPCRs ........................................................................................ 25 1.3. GPCR signaling ..................................................................................................... 26 2. The oxytocin and the vasopressin GPCRs .................................................................... 30 2.1. The oxytocin receptor ............................................................................................ 30 2.2. The vasopressin V1a receptor ................................................................................. 31 2.3. The vasopressin V1b receptor ................................................................................. 31 2.4. The vasopressin V2 receptor .................................................................................. 31 2.5. The endogenous ligands: oxytocin and vasopressin .............................................. 32 2.6. Central roles of oxytocin and vasopressin ............................................................. 33 Research objectives .............................................................................................................. 40 PART I. PET radiotracers for the oxytocin and the vasopressin V1a receptors ....................... 42 1. Positron emission tomography ...................................................................................... 43 1.1. Principles of positron emission tomography .......................................................... 43 1.2. Applications of PET to drug discovery .................................................................. 45 1.3. Criteria for an effective radioligand for a GPCR ................................................... 46 1.4. PET radiotracers for OT and AVP receptors ......................................................... 47 2. [11C] Carbetocin (CBT) ................................................................................................. 50 3. [11C] Relcovaptan (SR49059) ....................................................................................... 54 3. [11C] PF-3274167 .......................................................................................................... 61 4. [18F] derivative of PF-3274167 ..................................................................................... 64 5. Conclusion and perspectives ......................................................................................... 68 PART II. Fluorescent probes for the oxytocin and the vasopressin receptors ......................... 69 Introduction to fluorescence ................................................................................................. 70 Fluorescence methods to study ligand-receptor binding ...................................................... 71 ~ 2 ~ Chapter 1. Fluorescent probes for binding studies ................................................................... 75 Fluorescent ligands for TR-FRET assays ............................................................................. 76 1. Tb (III)–labeled ligands ............................................................................................. 76 2. First selective non-peptide fluorescent probes for the oxytocin receptor .................. 83 Turn-on fluorescent probes for native G protein-coupled receptors .................................... 88 1. Turn-on Nile red-based probes for OTR (Karpenko et al., 2014) ............................. 88 2. Turn-on squaraine-based probes for OTR ............................................................... 102 3. Squaraine-dimers as a new concept of fluorogenic probes ..................................... 110 Conclusion and perspectives .............................................................................................. 124 Chapter 2. Fluorescent probes for selectivity assays (profiling) ............................................ 125 Development of multicolor TR-FRET binding assay ......................................................... 126 Conclusion and perspectives .............................................................................................. 137 General conclusion and perspectives ..................................................................................... 138 Experimental part ................................................................................................................... 139 Part I: PET radiotracers for the oxytocin and the vasopressin V1a receptors ..................... 140 1. Chemical synthesis .................................................................................................. 140 2. Pharmacological evaluations of 1.33 ....................................................................... 153 3. Radiolabelling .......................................................................................................... 156 4. In vitro autoradiography studies .............................................................................. 157 Part II Chapter 1: Fluorescent probes for binding studies .................................................. 159 1. Tb (III)–labeled ligands ........................................................................................... 159 2. First selective non-peptide fluorescent probes for the oxytocin receptor ................ 163 3. Turn-on Nile red-based probes for OTR ................................................................. 169 4. Turn-on squaraine-based probes for OTR ............................................................... 178 5. Squaraine-dimers as a new concept of fluorogenic probes ..................................... 183 Part II Chapter 2: Fluorescent probes for selectivity assays (profiling) ............................. 188 1. Synthesis .................................................................................................................. 188 2. Affinity of the ligands 3.6, 3.7, 3.9 and 3.10 for V2R ............................................. 189 3. Multicolor binding assays ........................................................................................ 189 References .............................................................................................................................. 192 ~ 3 ~ Remerciements Au terme de ce travail je tiens à remercier chaleureusement le Prof. Marcel Hibert, mon directeur de thèse, de m’avoir confié ce sujet passionnant. Je te remercie pour ton enthousiasme, ton positivisme et ta foi en moi, pour tout ce que tu m’as appris ainsi que pour le temps que tu m’as consacré. Je remercie tout particulièrement le Dr. Dominique Bonnet pour m’avoir encadré tout au long de ma thèse. Merci pour ta disponibilité, tes conseils précieux qui m’ont fait avancer à grands pas, merci d’avoir toujours été un exemple du chercheur que je veux devenir. Je tiens à remercier le Dr. Francine
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