Asymmetric synthesis and preliminary evaluation of ( R)- and ( S)-[ 11C]bisoprolol, a putative β 1-selective adrenoceptor radioligand

Abstract

(±)-1-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2-propanol (bisoprolol) is a potent, clinically used β 1-adrenergic agent. ( R)-(+) and ( S)-(−) enantiomers of bisoprolol were labelled with carbon-11 ( t 1/2=20.4 min) as putative tracers for the non-invasive assessment of the β 1-adrenoceptor subtype in the human heart and brain with positron emission tomography (PET). The radiosynthesis consisted of reductive alkylation of des- iso-propyl precursor with [2- 11C]acetone in the presence of sodium cyanoborohydride and acetic acid. The stereo-conservative synthesis of ( R)-(+) and ( S)-(−)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-amino-2-propanol to be used as the precursors for the radiosynthesis of [ 11C]bisoprolol enantiomers was readily accomplished by the use of the corresponding chiral epoxide in three steps starting from the commercially available hydroxybenzyl alcohol. The final labelled product (either (+) or (−)-1-[4-(-isopropoxyethoxymethyl)-phenoxy]-3- [ 11C]isopropylamino-2-propanol) was obtained in 99% radiochemical purity in 30 min with 15±5% (EOS, non-decay corrected) radiochemical yield and 3.5±1 Ci/μmol specific radioactivity. Preliminary biological evaluation of the tracer in rats showed that about 30% of heart uptake of [ 11C]( S)-bisoprolol is due to specific binding. The high non-specific uptake in lung might mask the heart uptake, thus precluding the use of [ 11C]( S)-bisoprolol for heart and lung studies by PET. The remarkably high uptake of the tracer in rat brain areas rich of β-adrenergic receptors such as pituitary (1.8±0.3% I.D. at 30 min) was blocked by pre-treatment with the β-adrenergic antagonists propranolol (45%) and bisoprolol (51%, p<0.05). [ 11C]( S)-bisoprolol deserves further evaluation in other animal models as a putative β 1 selective radioligand for in vivo investigation of central adrenoceptors.