title: Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers.
abstract: The work described herein aims at finding new potential ligands for the brain imaging of 5-HT(4) receptors (5-HT(4)Rs) using single-photon emission computed tomography (SPECT). Starting from the nonsubstituted phenanthridine compound 4a, exhibiting a K(i) value of 51 nM on the 5-HT(4)R, we explored the structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to an increase of both the affinity and selectivity for 5-HT(4)R, suggesting the design of the antagonist 4v, exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT(4)R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[(123)I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate {[(123)I]1, [(123)I]SB 207710} both in vitro and in vivo in brain. Compound 11d was radiolabeled with [(125)I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT(4)R.
authors.affiliation: UFR des Sciences Pharmaceutiques, Université de Caen Basse-Normandie, EA 4258 CERMN, FR CNRS 3038 INC3M, SF-4206 ICORE, Boulevard Becquerel, F-14032 Caen, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Dubost
authors.forename: Noé
authors.initials: N
authors.lastname: Dumas
authors.forename: Christine
authors.initials: C
authors.lastname: Fossey
authors.forename: Rosa
authors.initials: R
authors.lastname: Magnelli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Butt-Gueulle
authors.forename: Céline
authors.initials: C
authors.lastname: Ballandonne
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Caignard
authors.forename: Fabienne
authors.initials: F
authors.lastname: Dulin
authors.forename: Jana
authors.initials: J
authors.lastname: Sopkova de-Oliveira Santos
authors.forename: Philippe
authors.initials: P
authors.lastname: Millet
authors.forename: Yves
authors.initials: Y
authors.lastname: Charnay
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: Thomas
authors.initials: T
authors.lastname: Cailly
authors.forename: Frederic
authors.initials: F
authors.lastname: Fabis
mesh_terms: D000818:Animals; D004146:Dioxanes / Q000494:pharmacology*; D015195:Drug Design; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D051379:Mice; D015335:Molecular Probes; D010880:Piperidines / Q000494:pharmacology*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry* / Q000378:metabolism; D058832:Serotonin 5-HT4 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D004146:Dioxanes; D007457:Iodine Radioisotopes; D008024:Ligands; D015335:Molecular Probes; D010880:Piperidines; D019275:Radiopharmaceuticals; C088873:SB 207710; D058832:Serotonin 5-HT4 Receptor Antagonists; D044422:Receptors, Serotonin, 5-HT4