title: Characterisation of beta2-adrenoceptors, using the agonist [11C]formoterol and positron emission tomography.
abstract: The agonist radioligand N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-[11C]-methoxyphenyl)-1-methylethyl]am ino]ethyl]phenyl]formamide ([11C]formoterol) was synthesised in order to test its ability to visualise pulmonary beta2-adrenoceptors in vivo, with positron emission tomography (PET). Formoterol was labelled via reaction of a dibenzyl-protected precursor with [11C]CH3I. Subsequent deprotection with Pd/C and H2 yielded [11C]formoterol in 5-15% (corrected for decay) and the specific activity ranged from 5.5-22.2 TBq mmol (150-600 Ci mmol(-1)), 60-70 min after end of bombardment. Biodistribution studies with [11C]formoterol were performed in male Wistar rats which were either untreated or predosed with (D,L)-propranolol hydrochloride (2.5 mg kg(-1), beta-adrenoceptor antagonist), erythro-DL-1-(7-methylindan-4-yloxy)-3-isopropylaminobuta n-2-ol hydrochloride (ICI 118551, 0.15 mg kg(-1), beta2-adrenoceptor antagonist), isoprenaline (15 mg kg(-1), non-subtype selective beta-adrenoceptor agonist) or (+/-)-(2-hydroxy-5-[2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1H-i midazol-2-yl-)phenoxy)propyl)amino)ethoxy]benzamide)monomethane sulfonate (CGP 20712A, 0.15 mg kg(-1), beta1-adrenoceptor antagonist). Lungs, heart, liver and plasma were analysed for radioactive metabolites. The kinetics of [11C]formoterol in the lungs of male Wistar rats were investigated by means of a dynamic PET study. The biodistribution studies showed significant specific binding in tissues known to contain beta2-adrenoceptors (lungs, spleen, and heart). Binding in these organs was blocked by ICI 118551 and isoprenaline, but not by CGP 20712A. [11C]Formoterol was rapidly metabolised in rats but lungs and heart did not substantially take up the labelled metabolites. The binding of [11C]formoterol in various tissues of rats is consistent with the beta2-selectivity of formoterol. Whether [11C]formoterol selectively binds to the high affinity state of beta2-adrenoceptors remains to be elucidated. [11C]Formoterol is potentially useful for studying beta2-adrenoceptors with PET and this radioligand may provide new insights in the mechanisms underlying prolonged sympathomimetic action.
authors.affiliation: Positron Emission Tomography (PET) Center, Groningen University Hospital, The Netherlands. t.j.visser@pet.azg.nl
authors.forename: T J
authors.initials: TJ
authors.lastname: Visser
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: T W
authors.initials: TW
authors.lastname: van der Mark
authors.forename: J
authors.initials: J
authors.lastname: Kraan
authors.forename: K
authors.initials: K
authors.lastname: Ensing
authors.forename: W
authors.initials: W
authors.lastname: Vaalburg
mesh_terms: D000318:Adrenergic beta-Agonists / Q000097:blood / Q000493:pharmacokinetics*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002250:Carbon Radioisotopes; D004983:Ethanolamines / Q000097:blood / Q000493:pharmacokinetics*; D000068759:Formoterol Fumarate; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002250:Carbon Radioisotopes; D004983:Ethanolamines; D007093:Imidazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; D011433:Propranolol; C049763:CGP 20712A; D007545:Isoproterenol; D000068759:Formoterol Fumarate