Pharmacologic 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 tomography were investigated.


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 mumol 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 x 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 beta-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.
Dubois
E A
EA
Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
Somsen
G A
GA
van den Bos
J C
JC
Janssen
A G
AG
Boer
G J
GJ
Batink
H D
HD
van Royen
E A
EA
Pfaffendorf
M
M
van Zwieten
P A
PA
D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000000981:diagnostic imaging; D006339:Heart Rate / Q000502:physiology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009248:Nadolol / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011412:Propanolamines / Q000493:pharmacokinetics; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
D000319:Adrenergic beta-Antagonists; D007457:Iodine Radioisotopes; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D009248:Nadolol; C033394:CGP 12177