title: Design of a serotonin 4 receptor radiotracer with decreased lipophilicity for single photon emission computed tomography.
abstract: With the aim to develop a suitable radiotracer for the brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed tomography (SPECT), we synthesized and evaluated a library of di- and triazaphenanthridines with lipophilicity values which were in the range expected to favour brain penetration, and which demonstrated specific binding to the target of interest. Adding additional nitrogen atoms to previously described phenanthridine ligands exhibiting a high unspecific binding, we were able to design a radioiodinated compound [(125)I]14. This compound exhibited a binding affinity value of 0.094 nM toward human 5-HT4R and a high selectivity over other serotonin receptor subtypes (5-HTR). In vivo SPECT imaging studies and competition experiments demonstrated that the decreased lipophilicity (in comparison with our previously reported compounds 4 and 5) allowed a more specific labelling of the 5-HT4R brain-containing regions.
authors.affiliation: Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fresneau
authors.affiliation: Hôpitaux Universitaires de Genève, Département de Santé Mentale et de Psychiatrie, Service de Psychiatrie Générale, Unité des Biomarqueurs de Vulnérabilité, Chemin du Petit-Bel-Air, 2, CH-1225 Genève, Switzerland.
authors.forename: Noé
authors.initials: N
authors.lastname: Dumas
authors.affiliation: Hôpitaux Universitaires de Genève, Département de Santé Mentale et de Psychiatrie, Service de Psychiatrie Générale, Unité des Biomarqueurs de Vulnérabilité, Chemin du Petit-Bel-Air, 2, CH-1225 Genève, Switzerland.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Tournier
authors.affiliation: Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Fossey
authors.affiliation: Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Ballandonne
authors.affiliation: Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lesnard
authors.affiliation: Hôpitaux Universitaires de Genève, Département de Santé Mentale et de Psychiatrie, Service de Psychiatrie Générale, Unité des Biomarqueurs de Vulnérabilité, Chemin du Petit-Bel-Air, 2, CH-1225 Genève, Switzerland.
authors.forename: Philippe
authors.initials: P
authors.lastname: Millet
authors.affiliation: Hôpitaux Universitaires de Genève, Département de Santé Mentale et de Psychiatrie, Service de Psychiatrie Générale, Unité des Biomarqueurs de Vulnérabilité, Chemin du Petit-Bel-Air, 2, CH-1225 Genève, Switzerland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Charnay
authors.affiliation: Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cailly
authors.affiliation: Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France. Electronic address: jean-philippe.bouillon@univ-rouen.fr.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Bouillon
authors.affiliation: Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France. Electronic address: frederic.fabis@unicaen.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fabis
mesh_terms: D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D007457:Iodine Radioisotopes; D008024:Ligands; D010617:Phenanthridines; D019275:Radiopharmaceuticals; D044422:Receptors, Serotonin, 5-HT4
keywords: 5-HT; Iodine; Molecular imaging; Radiolabeling; SPECT; Serotonin