Characterisation of β 2-adrenoceptors, using the agonist [ [formula omitted]]formoterol and positron emission tomography

Abstract

The agonist radioligand N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4- [ 11 C] -methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide ( [ 11 C] formoterol) was synthesised in order to test its ability to visualise pulmonary β 2-adrenoceptors in vivo, with positron emission tomography (PET). Formoterol was labelled via reaction of a dibenzyl-protected precursor with [ 11 C] CH 3I. Subsequent deprotection with Pd/C and H 2 yielded [ 11 C] formoterol in 5–15% (corrected for decay) and the specific activity ranged from 5.5–22.2 TBq mmol −1 (150–600 Ci mmol −1), 60–70 min after end of bombardment. Biodistribution studies with [ 11 C] formoterol were performed in male Wistar rats which were either untreated or predosed with ( d, l)-propranolol hydrochloride (2.5 mg kg −1, β-adrenoceptor antagonist), erythro- dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol hydrochloride (ICI 118551, 0.15 mg kg −1, β 2-adrenoceptor antagonist), isoprenaline (15 mg kg −1, non-subtype selective β-adrenoceptor agonist) or (±)-(2-hydroxy-5-[2-((2-hydroxy-3-(4-((1-methyl-4-trifluoromethyl)1 H-imidazol-2-yl-)phenoxy)propyl)amino)ethoxy]benzamide)monomethane sulfonate (CGP 20712A, 0.15 mg kg −1, β 1-adrenoceptor antagonist). Lungs, heart, liver and plasma were analysed for radioactive metabolites. The kinetics of [ 11 C] 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 β 2-adrenoceptors (lungs, spleen, and heart). Binding in these organs was blocked by ICI 118551 and isoprenaline, but not by CGP 20712A. [ 11 C] Formoterol was rapidly metabolised in rats but lungs and heart did not substantially take up the labelled metabolites. The binding of [ 11 C] formoterol in various tissues of rats is consistent with the β 2-selectivity of formoterol. Whether [ 11 C] formoterol selectively binds to the high affinity state of β 2-adrenoceptors remains to be elucidated. [ 11 C] Formoterol is potentially useful for studying β 2-adrenoceptors with PET and this radioligand may provide new insights in the mechanisms underlying prolonged sympathomimetic action.