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

(±)-1-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2-pro panol (bisoprolol) is a potent, clinically used β1-adrenergic agent. (R)-(+) and (S)-(-) enantiomers of bisoprolol were labelled with carbon-11 (t1/2 = 20.4 min) as putative tracers for the non-invasive assessment of the β1-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 β1 selective radioligand for in vivo investigation of central adrenoceptors.