title: Synthesis and in vitro and in vivo characteristics of an iodinated analogue of the beta-adrenoceptor antagonist carazolol.
abstract: A new (radio)iodinated, beta-adrenoceptor ligand, (S)-(-)-4-[3-[(1,1-dimethyl-3-iodo-(2E)-propenyl)-amino]-2- hydroxypropoxy]carbazole (CYBL8E, 1), was prepared. 1 is an iodinated analogue of the high-affinity beta-adrenoceptor antagonist carazolol (2). The asymmetric synthesis was achieved in four steps starting from 4-hydroxycarbazole. The iodine-123-labeled form was obtained by an iododestannylation reaction with [123I]NaI in the presence of H2O2. Using classical in vitro displacement experiments with membrane fractions of cardiac left ventricular muscle, 1 proved to have a high affinity for the receptor (Ki = 0.31 +/- 0.03). Biodistribution studies performed in New Zealand white rabbits demonstrated the specificity of the binding in vivo to the receptor. Uptake of [123I]1 was reduced significantly in both atrial muscle, left ventricular muscle, frontal cortex, cerebellum, and striatum, by the pretreatment of the animals with different beta-adrenoceptor antagonists. In conclusion, 1 is a potent nonselective beta-adrenoceptor antagonist, which binds specifically to the beta-adrenoceptor in vivo, and is therefore a promising radioligand for the imaging of beta-adrenoceptors using single photon emission computerized tomography.
authors.affiliation: Department of Nuclear Medicine, University of Amsterdam, The Netherlands. E.A.Dubois@amc.uva.nl
authors.forename: E A
authors.initials: EA
authors.lastname: Dubois
authors.forename: J C
authors.initials: JC
authors.lastname: van den Bos
authors.forename: T
authors.initials: T
authors.lastname: Doornbos
authors.forename: P A
authors.initials: PA
authors.lastname: van Doremalen
authors.forename: G A
authors.initials: GA
authors.lastname: Somsen
authors.forename: J A
authors.initials: JA
authors.lastname: Vekemans
authors.forename: A G
authors.initials: AG
authors.lastname: Janssen
authors.forename: H D
authors.initials: HD
authors.lastname: Batink
authors.forename: G J
authors.initials: GJ
authors.lastname: Boer
authors.forename: M
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: E A
authors.initials: EA
authors.lastname: van Royen
authors.forename: P A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002227:Carbazoles / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D006352:Heart Ventricles; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011412:Propanolamines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D007202:Indicators and Reagents; D007457:Iodine Radioisotopes; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C100990:4-(3-((1,1-dimethyl-3-iodopropenyl)amino)-2-hydroxypropoxy)carbazole; C014382:carazolol; C026777:ICI 118551; C033394:CGP 12177