Synthesis and biodistribution of [C-11]procaterol, a beta(2)-adrenoceptor agonist for positron emission tomography

The potent, subtype-selective radioligand (+/-)-erythro-5-(1-hydroxy-2-[C-11]isopropyl-aminobutyl)-8-hydroxy-carbostyril ([C-11]procaterol) was synthesized and evaluated for visualization of pulmonary beta(2)-adrenoceptors with positron emission tomography (PET). Procaterol was labelled by reductive alkylation of the desisopropyl precursor with [C-11]acetone under the influence of NaCNBH3 and acetic acid. Synthesis and HPLC purification were performed in 34 min. Specific activities ranged from 26.5-39.3 TBq (about 700-1000 Ci)/mmol and the radiochemical yield was 2.4-8.6% (corrected for decay). Biodistribution studies were performed in male Wistar rats which were either untreated or predosed with (D,L)-propranolol hydrochloride (beta-adrenoceptor antagonist, 2.5 mg/kg), ICI 118551 (beta(2)-adrenoceptor antagonist, 0.15 mg/ kg), CGP 20712A (beta(1)-adrenoceptor antagonist, 0.15; mg/kg) or isoprenaline (B-adrenoceptor agonist, 15 mg/kg). Specific binding was observed in lungs, spleen and red blood cells, tissues known to contain beta(2)-adrenoceptors. Pulmonary binding was blocked by propranolol, ICI 118551 and isoprenaline, but not by CGP 20712A. This binding pattern is consistent with the beta(2) selectivity of the adioligand. The clearance of [C-11]procaterol was biphasic, with a rapid distribution phase (t(1/2) 0.17 min) representing 90% of the injected dose followed by an elimination phase (t(1/2) 18.1 min). About 45% of the plasma radioactivity was unmetabolized procaterol at 15 min postinjection. In a dynamic PET-study, the lungs of untreated control rats could barely be detected and total/non-specific binding ratios rose to only 1.2 at 20 min postinjection. Although labelling and administration of (-) erythro-procaterol the most active of 4 stereoisomers, may produce better results, [C-11]procaterol seems unsuitable for beta-adrenoceptor imaging. (C) 2000 Elsevier Science Ltd. All rights reserved