PHARMACOLOGICAL CHARACTERIZATION IN-VITRO AND IN-VIVO OF IODINE 123-LABELED DERIVATIVES OF THE BETA-ADRENOCEPTOR ANTAGONIST CGP12177, DESIGNED FOR THE IMAGING OF CARDIAC BETA-RECEPTORS

Background. Potential new radioligands for the noninvasive imaging of cardiac beta-adrenoceptors with single-photon emission computed tomogr aphy were investigated. Methods and Results. Two iodinated derivatives of CGP12177 para (S-CYBL2B) and ortho (CYBL2A) substituted CGP12177 a nd an iodinated form of nadolol (CYBL1) were synthesized. Their affini ty was tested in vitro (left ventricular homogenates). The biodistribu tion of [I-123]S-CYBL2B was evaluated in rabbits. Specific binding was assessed by pretreatment of the animals with 0.1 mu mol 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 [I-123]S-CYBL2B was not inhibited by pretreatment of the animals with propranolol, but uptake by lung tissu e could be blocked by propranolol (0.63% +/- 0.09% vs 0.33% +/- 0.02% % injected dose/g x kg; p < 0.05). In isolated right atria, preincubat ion with S-CYBL2B induced a parallel rightward shift of the concentrat ion-response curve with isoprenaline. Conclusions. S-CYBL2B shows high affinity for cardiac beta-adrenoceptors, but binding proved nonspecif ic in vivo, whereas binding in lung tissue was specific. These results suggest that S-CYBL2B is probably not a suitable radioligand for rece ptor imaging.