Demonstration of the suitability of CGP 12177 for in vivo studies of beta-adrenoceptors.

1. Positron emission tomography (PET) with appropriate radioligands offers the possibility of studying receptors non-invasively in man. The suitability of CGP 12177, a hydrophilic non-selective beta-adrenoceptor antagonist which can be labelled with the positron emitter 11C, as a ligand for in vivo studies of beta-adrenoceptors was assessed in rats. 2. [3H]-CGP 12177 was injected into the tail veins of restrained conscious rats. Serial blood samples were taken from tail arteries to determine clearance from plasma. Rats were killed and tissues removed to determine tissue uptake. Radioactivity was assessed by liquid scintillation counting. 3. The uptake of (-)-[3H]-CGP 12177 in various tissues was compared to that of (+/-)-[3H]-CGP 12177. Maximum tissue:plasma ratios obtained for the (-)-enantiomer in lung, heart and liver were 170, 42 and 13 compared with 60, 15 and 12 for the racemate. Prior injection of excess unlabelled (+/-)-CGP 12177 blocked the uptake of both (-)- and (+/-)-[3H]-CGP 12177 in lung and heart but not liver, tissue:plasma ratios for both tracers being reduced to 7, 3 and 7 respectively. 4. Clearance of (-)-[3H]-CGP 12177 from plasma was rapid during the first 5 min but showed only small changes during 5 to 90 min. Uptake in lung and heart reached a maximum at 1 to 5 min and showed a slow decrease during 5-90 min. Prior injection of unlabelled (+/-)-CGP 12177 reduced uptake in lung and heart to 10% and 20% respectively. Injection of unlabelled ( +/-)-CGP 12177 at 15 mind is placed ~75% of the radioactivity by 90 min.5. ( +/- )-Propranolol had a similar effect to that of unlabelled ( +/-)-CGP 12177. Prior injection reduced uptake of radioactivity in lung and heart to 15% and 20% respectively. Injection of ( +/- )-propranolol at 15 min displaced ~ 60% of the radioactivity by 90 min indicating that the tracer binds to beta-adrenoceptor sites in vivo.6. In vivo saturation curves, obtained by injection of (-)-[3H]-CGP 12177 with increasing amounts of unlabelled (- )-CGP 12177, gave values of Bmax for lung of ~45 pmol per g wet weight of tissue and for heart of ~6 pmol per g wet weight of tissue. KD could only be expressed as nmol injected per kg bodyweight, that for lung (2.5 nmol kg-1) being greater than that for heart (1.3 nmol kg-1).7. Competition studies carried out by co-injecting (-)-[3H]-CGP 12177 with unlabelled (+/- )-CGP12177 or (-)-propranolol gave similar values for Bmax (lung 44 pmol g-1, heart 6 pmol g-1,). Values of KD for (+/-)-CGP 12177 (lung 4.7 pmol kg-1, heart 2.6 pmol kg-1) were approximately twice those for(-)-CGP 12177. Values of KD for (-)-propranolol (lung 38 nmol kg-1, heart 104 nmol kg-1) were greater.8. The results show that (-)-[3H]-CGP 12177 is a suitable ligand for assessing beta-adrenoceptors in vivo.