title: Asymmetric synthesis and preliminary evaluation of (R)- and (S)-[11C]bisoprolol, a putative beta1-selective adrenoceptor radioligand.
abstract: (+/-)-1-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2-propanol (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 beta(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/micromol 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 beta-adrenergic receptors such as pituitary (1.8+/-0.3% I.D. at 30 min) was blocked by pre-treatment with the beta-adrenergic antagonists propranolol (45%) and bisoprolol (51%, p<0.05). [11C](S)-bisoprolol deserves further evaluation in other animal models as a putative beta(1) selective radioligand for in vivo investigation of central adrenoceptors.
authors.affiliation: INB-CNR, University of Milano-Bicocca, Italy.
authors.forename: D V
authors.initials: DV
authors.lastname: Soloviev
authors.forename: M
authors.initials: M
authors.lastname: Matarrese
authors.forename: R M
authors.initials: RM
authors.lastname: Moresco
authors.forename: S
authors.initials: S
authors.lastname: Todde
authors.forename: T A
authors.initials: TA
authors.lastname: Bonasera
authors.forename: F
authors.initials: F
authors.lastname: Sudati
authors.forename: P
authors.initials: P
authors.lastname: Simonelli
authors.forename: F
authors.initials: F
authors.lastname: Magni
authors.forename: D
authors.initials: D
authors.lastname: Colombo
authors.forename: A
authors.initials: A
authors.lastname: Carpinelli
authors.forename: M G
authors.initials: MG
authors.lastname: Kienle
authors.forename: F
authors.initials: F
authors.lastname: Fazio
mesh_terms: D000818:Animals; D017298:Bisoprolol / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D008024:Ligands; D008168:Lung / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D011943:Receptors, Adrenergic, beta; D017298:Bisoprolol