Synthesis and in Vitro and in Vivo Characteristics of an Iodinated Analogue of the β-Adrenoceptor Antagonist Carazolol

A new (radio)iodinated, β-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 β-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 (K i = 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 β-adrenoceptor antagonists. In conclusion, 1 is a potent nonselective β-adrenoceptor antagonist, which binds specifically to the β-adrenoceptor in vivo, and is therefore a promising radioligand for the imaging of β-adrenoceptors using single photon emission computerized tomography.