Pharmacologic characterization in vitro and in vivo of iodine 123-labeled derivatives of the β-adrenoceptor antagonist CGP 12177, designed for the imaging of cardiac β-receptors

Background  Potential new radioligands for the noninvasive imaging of cardiac β-adrenoceptors with single-photon emission computed tomography were investigated. Methods and Results  Two iodinated derivatives of CGP12177 para (S-CYBL2B) and ortho (CYBL2A) substituted CGP12177 and an iodinated form of nadolol (CYBL1) were synthesized. Their affinity was tested in vitro (left ventricular homogenates). The biodistribution of [123I]S-CYBL2B was evaluated in rabbits. Specific binding was assessed by pretreatment of the animals with 0.1 μmol propranolol. The inhibition constant values (in nanomolars, means±SEM; n=3 to 5) were determined at 1.17±0.42, 28800±9260, 11.1±2.1, 53.0±19.9, and 1790±700 for CGP12177, CYBL2A, S-CYBL2B, nadolol, and CYBL1. Myocardial uptake of [123I]S-CYBL2B was not inhibited by pretreatment of the animals with propranolol, but uptake by lung tissue could be blocked by propranolol (0.63%±0.09% vs 0.33%±0.02% % injected dose/g×kg; p<0.05). In isolated right atria, preincubation with S-CYBL2B induced a parallel rightward shift of the concentration-response curve with isoprenaline. Conclusions  S-CYBL2B shows high affinity for cardiac β-adrenoceptors, but binding proved nonspecific in vivo, whereas binding in lung tissue was specific. These results suggest that S-CYBL2B is probably not a suitable radioligand for receptor imaging.