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

(+/-)-1-[4-(2-Isopropoxylethuxymethyl)-phenoxyl]-3-isopropylamino-2-propano l (bisoprolol) is a potent, clinically used beta (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 beta1-adrenoceptor subtype in the human heart and brain with positron emiss ion tomography (PET). The radiosynthesis consisted of reductive alkylation of des-iso-propyl precursor with [2-C-11]acetone in the presence of sodium cyanoborohydride and acetic acid. The stereo-conservative synthesis of (R)- (+) and (S)-(-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxyl-3-amino-2-propanol to be used as the precursors for the radiosynthesis of [C-11]bisoprolol en antiomcrs was readily accomplished by the use of the corresponding chiral e poxide in three steps starting From the commercially available hydroxybenzy l alcohol. The final labelled product (either (+) or (-)- 1-[4-(-isopropoxq ;ethoxymethyl)phenoxy]-3- [C-11]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/mu mol specific radioactivity. Prelimina ry biological evaluation of the tracer in rats showed that about 30% of hea rt uptake of [C-11](S)-bisoprolol is due to specific binding. The high non- specific uptake in lung might mask the heart uptake, thus precluding the us e of [C-11](S)-bisoprolol for heart and lung studies by PET. The remarkably high uptake of the tracer in rat brain areas rich of P-adrenergic receptor s such as pituitary (1.8+/-0.3% I.D. at 30 min) was blocked by pre-treatmen t with the P-adrenergic antagonists propranolol (45%) and bisoprolol (51%, p< 0.05). [C-11](S)-bisoprolol deserves further evaluation in other animal models as a putative Pi selective radioligand for in vivo investigation of central adrenoceptors. (C) 2001 Elsevier Science Ltd. All rights reserved.