title: New alpha(1)-adrenoceptor antagonists derived from the antipsychotic sertindole - carbon-11 labelling and pet examination of brain uptake in the cynomolgus monkey.
abstract: Central alpha(1)-adrenergic receptors are potential targets for recently developed antipsychotic drugs. Two new 11C labeled potent and selective alpha(1)-adrenoceptor antagonists, 1- [2- [4-[1-(4-fluorophenyl)-5-(2-[(11)C]methyl-tetrazol-5-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]2) and 1- [2- [4-[1-(4-fluorophenyl)-5-(1-[(11)C]methyl-(1,2,3-triazol-4-yl)-1H-indol-3-yl]-1-piperidinyl]ethyl]-imidazolidin-2-one ([(11)C]3) were prepared and evaluated for imaging of central alpha(1)-adrenergic receptors in the cynomolgus monkey brain. For both compounds, the total brain radioactivity was only about 0.6% of the radioactivity injected i.v. There was no evident binding in regions known to contain alpha(1)-adrenoceptors. This observation suggests that the affinity of the radioligands in primates in vivo is not sufficient to provide a signal for specific binding that can be differentiated from the background. In addition, active efflux by P-glycoprotein may be responsible for the low total brain-uptake of the two radioligands. Both compounds showed a highly polarised and verapamile sensitive transport across monolayers of Caco-2 cells. The total brain-uptake of [(3)H]2 was 6 times higher in mdr1a(-/-) knock-out mice lacking the gene encoding P-glycoprotein compared to wild type mice. Pretreatment of one monkey with Cyclosporin A (15 mg/kg) resulted in 40% higher brain uptake for [(11)C]3 when compared with baseline. These observations support the view that efflux by P-glycoprotein can be of quantitative importance for the total brain-uptake of some PET radioligands.
authors.affiliation: Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-171 76 Stockholm, Sweden. tb@dfuni.dk
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Linus
authors.initials: L
authors.lastname: Andersen
authors.forename: Lene
authors.initials: L
authors.lastname: Hjorth Alifrangis
authors.forename: Lassina
authors.initials: L
authors.lastname: Badolo
authors.forename: Klaus
authors.initials: K
authors.lastname: Gjervig Jensen
authors.forename: Yuan-Wha
authors.initials: YW
authors.lastname: Chou
authors.forename: Kim
authors.initials: K
authors.lastname: Andersen
authors.forename: Jens
authors.initials: J
authors.lastname: Perregaard
authors.forename: Lars
authors.initials: L
authors.lastname: Farde
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency; D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D018938:Caco-2 Cells; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D007700:Kinetics; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D058668:Adrenergic alpha-1 Receptor Antagonists; D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D007093:Imidazoles; D007211:Indoles; D019275:Radiopharmaceuticals; D018340:Receptors, Adrenergic, alpha-1; D016572:Cyclosporine; C066304:sertindole