title: Synthesis and in vitro characterization of novel fluorinated derivatives of the TSPO 18 kDa ligand SSR180575.
abstract: SSR180575 (1) is a high-affinity (0.83 nM) TSPO 18 kDa ligand belonging to the pyridazino[4,5-b]indole-1-acetamides family. Herein we describe the synthesis and in vitro characterization of two series of new fluorinated analogues. Eleven compounds (out of fifteen) displayed nanomolar to subnamolar affinities (0.30-8.1 nM) and high selectivities (Ki(CBR)/Ki(TSPO) > 10(3)). Two derivatives stand out as promising candidates for drug development or use as PET probes for in vivo neuroinflammation imaging, once fluorine-18-labelled.
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France; Inserm / CEA / Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France. Electronic address: annelaure.damont@cea.fr.
authors.forename: Annelaure
authors.initials: A
authors.lastname: Damont
authors.affiliation: Exploratory Unit, Sanofi, Chilly-Mazarin, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Marguet
authors.affiliation: Exploratory Unit, Sanofi, Chilly-Mazarin, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Puech
authors.affiliation: CEA, I2BM, Service Hospitalier Frédéric Joliot, Orsay, France; Inserm / CEA / Université Paris Sud, UMR 1023 - ERL 9218 CNRS, IMIV, Orsay, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000378:metabolism*; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008861:Microsomes / Q000737:chemistry / Q000378:metabolism; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*
chemical_list: D000081:Acetamides; C463819:Bzrp protein, mouse; D005462:Fluorine Radioisotopes; D007211:Indoles; D015335:Molecular Probes; D018079:Receptors, GABA; C456740:SSR180575
keywords: Neuroinflammation; Positron emission tomography; SSR180575; TSPO 18 kDa; pyridazino[4,5-b]indole-1-acetamides