title: In vitro pharmacological properties of 4-bromodexetimide for muscarinic receptors.
abstract: The decrease of m-AChR density observed in neurodegenerative disorders has generated considerable interest in non-invasive mapping of muscarinic acetylcholine receptors (m-AChR) in the central nervous system. The aim of our study was to evaluate the selectivity of 4-bromodexetimide for the M1, M2, M3 and M4 m-AChR subtypes using in vitro binding analysis to determine the potential use of the bromine-76 labelled 4-bromodexetimide in the investigation of m-AChR subtypes in human brain with Positron Emission Tomography. Subtype selectivity of 4-bromodexetimide was determined in competition studies against tritiated subtype selective ligands using various rat or rabbit structure homogenates reflecting a single binding site and in optimal saturation and low non specific binding conditions. These conditions were reached for every subtype studied by analyzing the data from the saturation experiments of the tritiated ligands. 4-bromodexetimide displayed nanomolar affinities for the four m-AChR subtypes and a preferential selectivity for the M1 and M4 subtypes. The saturation analysis of [76Br]4-bromodexetimide, performed with rat cortex membranes showed high affinity for m-AChR receptors (Kd = 1.8 nM). As in vivo studies of [76Br]4-bromodexetimide showed preferential localization in the cortex and the striatum which are M1 and M4 rich structures and since it binds preferentially to the M1 and M4 subtypes, this radiotracer can still allow a combined subtype specific measurement of these muscarinic receptors.
authors.affiliation: Service Hospitalier Frederic Joliot, CEA, DSV/DRM, Orsay, France.
authors.forename: V
authors.initials: V
authors.lastname: Strijckmans
authors.forename: C
authors.initials: C
authors.lastname: Coulon
authors.forename: M
authors.initials: M
authors.lastname: Kassiou
authors.forename: C
authors.initials: C
authors.lastname: Loc'h
authors.forename: B
authors.initials: B
authors.lastname: Mazière
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D003909:Dexetimide / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D018727:Muscarinic Antagonists / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000145:classification / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism
chemical_list: D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C099688:4-bromodexetimide; D003909:Dexetimide