title: Synthesis and biodistribution of [11c]procaterol, a beta2-adrenoceptor agonist for positron emission tomography.
abstract: The potent, subtype-selective radioligand (+/-)-erythro-5-(1-hydroxy-2-[11C]isopropyl-aminobutyl)-8-hydroxy-car bostyril ([11C]procaterol) was synthesized and evaluated for visualization of pulmonary beta2-adrenoceptors with positron emission tomography (PET). Procaterol was labelled by reductive alkylation of the desisopropyl precursor with [11C]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 (beta2-adrenoceptor antagonist, 0.15 mg/kg), CGP 20712A (beta1-adrenoceptor antagonist, 0.15 mg/kg) or isoprenaline (beta1-adrenoceptor agonist, 15 mg/kg). Specific binding was observed in lungs, spleen and red blood cells, tissues known to contain beta2-adrenoceptors. Pulmonary binding was blocked by propranolol, ICI 118551 and isoprenaline, but not by CGP 20712A. This binding pattern is consistent with the beta2 selectivity of the radioligand. The clearance of [11C]procaterol was biphasic, with a rapid distribution phase (t1/2 0.17 min) representing 90% of the injected dose followed by an elimination phase (t1/2 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 (-) erythroprocaterol, the most active of 4 stereoisomers, may produce better results, [11C]procaterol seems unsuitable for beta-adrenoceptor imaging.
authors.affiliation: Positron Emission Tomography (PET) Center, Groningen University Hospital, The Netherlands.
authors.forename: T J
authors.initials: TJ
authors.lastname: Visser
authors.forename: E A
authors.initials: EA
authors.lastname: van der Wouden
authors.forename: A
authors.initials: A
authors.lastname: van Waarde
authors.forename: P
authors.initials: P
authors.lastname: Doze
authors.forename: P H
authors.initials: PH
authors.lastname: Elsinga
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
mesh_terms: D000318:Adrenergic beta-Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002250:Carbon Radioisotopes; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D017265:Procaterol / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011433:Propranolol / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis* / Q000378:metabolism; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002250:Carbon Radioisotopes; D018343:Receptors, Adrenergic, beta-2; D011433:Propranolol; D017265:Procaterol