title: Positron emission tomographic investigations of central muscarinic cholinergic receptors with three isomers of [76Br]BrQNP.
abstract: We studied the potential of three radiobrominated isomers of BrQNP, (Z(-,-)-[76Br]BrQNP, E(-,-)-[76Br]BrQNP and E(-,+)-[76Br]BrQNP), as suitable radioligands for imaging of central muscarinic cholinergic receptors in the human brain. These radioligands were stereospecifically prepared by electrophilic radiobromodestannylation of the respective tributylstannyl precursors using no-carrier-added [76Br]BrNH4 and peracetic acid. Preliminary pharmacological characterizations were determined by biodistribution, autoradiography, competition, displacement and metabolite studies in rats. The (-,-)-configuration presented important specific uptakes in brain muscarinic cholinergic receptor (mAChR)-rich structures and in heart, low metabolization rates and an apparent M2 selectivity. The (-,+)-configuration revealed more rapid clearance, lower uptake, a higher metabolization rate and an apparent M1 selectivity. Reversibility of the binding was confirmed for the three radiotracers. Positron emission tomography in the living baboon brain revealed high and rapid uptake in the brain and accumulation in the mAChR-rich structures studied. At 30 min p.i., the E(-,-)-radiotracer reached a plateau in cortex, pons and thalamus with concentrations of 29%, 24% and 19% ID/l, respectively. Z(-,-)-[76Br]BrQNP also accumulated in these structures, reaching a maximal uptake (27% ID/l) in the cortex 2 h p.i. At 5 min p.i. a plateau (17% ID/l) was only observed in the cortex for the E(-, +)-[76Br]BrQNP; by contrast, the other structures showed slow washout. After 3 weeks, the (-,-)-radiotracers were studied in the same baboon pretreated with dexetimide (1 mg/kg), a well-known muscarinic antagonist. In all the mAChR structures, the highly reduced uptake observed after this preloading step indicates that these radiotracers specifically bind to muscarinic receptors. Z(-, -)-[76Br]BrQNP, which is displaced in higher amounts from M2 mAChR-enriched structures, reveals an M2 affinity. The two isomers having the (-,-)-configuration are potential probes for investigating central muscarinic receptors. The absolute configuration on the acetate chiral centre influences their muscarinic subtype selectivity and the cis-trans isomerism of the vinyl moiety affects their specific fixation.
authors.affiliation: Service Hospitalier Frédéric Joliot, CEA, DRM, F-91406 Orsay, France.
authors.forename: V
authors.initials: V
authors.lastname: Strijckmans
authors.forename: M
authors.initials: M
authors.lastname: Bottlaender
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.forename: M
authors.initials: M
authors.lastname: Ottaviani
authors.forename: D W
authors.initials: DW
authors.lastname: McPherson
authors.forename: C
authors.initials: C
authors.lastname: Loc'h
authors.forename: C
authors.initials: C
authors.lastname: Fuseau
authors.forename: F F
authors.initials: FF
authors.lastname: Knapp
authors.forename: B
authors.initials: B
authors.lastname: Mazière
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D001967:Bromine Radioisotopes; D003909:Dexetimide / Q000494:pharmacology; D008297:Male; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D010215:Papio; D011813:Quinuclidinyl Benzilate / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000032:analysis*; D013237:Stereoisomerism; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D001967:Bromine Radioisotopes; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D003909:Dexetimide; D011813:Quinuclidinyl Benzilate