title: Radiolabelling and PET brain imaging of the α₁-adrenoceptor antagonist Lu AE43936.
abstract: Cerebral α₁-adrenoceptors are a common target for many antipsychotic drugs. Thus, access to positron emission tomography (PET) brain imaging of α₁-adrenoceptors could make important contributions to the understanding of psychotic disorders as well as to the pharmacokinetics and occupancy of drugs targeting the α₁-adrenoceptors. However, so far no suitable PET radioligand has been developed for brain imaging of α₁-adrenoceptors. Here, we report the synthesis of both enantiomers of the desmethyl precursors of the high affinity α₁-adrenoceptor ligand (1). The two enantiomers of 1 were subsequently [¹¹C] radiolabelled and evaluated for brain uptake and binding by PET imaging in Danish Landrace pigs. (S)-[¹¹C]-1 and (R)-[¹¹C]-1 showed very limited brain uptake. Pre-treatment with cyclosporine A (CsA) resulted in a large increase in brain uptake, indicating that (R)-[¹¹C]-1 is a substrate for active efflux-transporters. This was confirmed in Madin Darby canine kidney (MDCK) cells overexpressing permeability glycoprotein (Pgp). In conclusion, the limited brain uptake of both (S)-[¹¹C]-1 and (R)-[¹¹C]-1 in the pig brain necessitates the search for alternative radioligands for in vivo PET brain imaging of α₁-adrenoceptors.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Rune
authors.initials: R
authors.lastname: Risgaard
authors.forename: Anders
authors.initials: A
authors.lastname: Ettrup
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Agnete
authors.initials: A
authors.lastname: Dyssegaard
authors.forename: Hanne Demant
authors.initials: HD
authors.lastname: Hansen
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.forename: Henrik
authors.initials: H
authors.lastname: Pedersen
authors.forename: Ask
authors.initials: A
authors.lastname: Püschl
authors.forename: Lassina
authors.initials: L
authors.lastname: Badolo
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: Gitte Moos
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Jesper Langgaard
authors.initials: JL
authors.lastname: Kristensen
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D003988:Dibenzothiepins / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D004285:Dogs; D005260:Female; D007553:Isotope Labeling; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D049268:Positron-Emission Tomography / Q000379:methods*; D011854:Radiochemistry; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D003988:Dibenzothiepins; D008024:Ligands; C581142:Lu AE43936; D018340:Receptors, Adrenergic, alpha-1; C100288:octoclothepine