Synthesis and in vitro and in vivo characteristics of an iodinated analogue of the beta-adrenoceptor antagonist carazolol.
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.
Dubois
E A
EA
Department of Nuclear Medicine, University of Amsterdam, The Netherlands. E.A.Dubois@amc.uva.nl
van den Bos
J C
JC
Doornbos
T
T
van Doremalen
P A
PA
Somsen
G A
GA
Vekemans
J A
JA
Janssen
A G
AG
Batink
H D
HD
Boer
G J
GJ
Pfaffendorf
M
M
van Royen
E A
EA
van Zwieten
P A
PA
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
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