title: Radiosynthesis and Evaluation of [11C]3-Hydroxycyclopent-1-enecarboxylic Acid as Potential PET Ligand for the High-Affinity γ-Hydroxybutyric Acid Binding Sites.
abstract: γ-Hydroxybutyric acid (GHB) is an endogenous neuroactive substance and proposed neurotransmitter with affinity for both low- and high-affinity binding sites. A radioligand with high and specific affinity toward the high-affinity GHB binding site would be a unique tool toward a more complete understanding of this population of binding sites. With its high specific affinity and monocarboxylate transporter (MCT1) mediated transport across the blood-brain barrier in pharmacological doses, 3-hydroxycyclopent-1-enecarboxylic acid (HOCPCA) seems like a suitable PET radiotracer candidate. Here, we report the11C-labeling and subsequent evaluation of [11C]HOCPCA in a domestic pig, as a PET-radioligand for visualization of the high-affinity GHB binding sites in the live pig brain. To investigate the regional binding of HOCPCA in pig brain prior to in vivo PET studies, in vitro quantitative autoradiography on sections of pig brain was performed using [3H]HOCPCA. In vivo evaluation of [11C]HOCPCA showed no brain uptake, possibly due to a limited uptake of HOCPCA by the MCT1 transporter at tracer doses of [11C]HOCPCA.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Claus H
authors.initials: CH
authors.lastname: Jensen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen , Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Hanne D
authors.initials: HD
authors.lastname: Hansen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Bay
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Stine B
authors.initials: SB
authors.lastname: Vogensen
authors.affiliation: PET and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet , Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Lehel
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Louise
authors.initials: L
authors.lastname: Thiesen
authors.affiliation: Discovery DMPK, H. Lundbeck A/S , Ottiliavej, 2500 Valby, Denmark.
authors.forename: Christoffer
authors.initials: C
authors.lastname: Bundgaard
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Rasmus P
authors.identifier: 0000-0001-9466-9431
authors.initials: RP
authors.lastname: Clausen
authors.affiliation: Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen , Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.|Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Rigshospitalet and University of Copenhagen , Blegdamsvej 9, 2100 Copenhagen, Denmark.|PET and Cyclotron Unit, Copenhagen University Hospital, Rigshospitalet , Blegdamsvej 9, 2100 Copenhagen, Denmark.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Herth
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Petrine
authors.initials: P
authors.lastname: Wellendorph
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Frølund
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects*; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects*; D002247:Carbon Isotopes / Q000737:chemistry / Q000493:pharmacokinetics; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D013552:Swine
chemical_list: C586846:3-hydroxycyclopent-1-enecarboxylic acid; D002247:Carbon Isotopes; D002264:Carboxylic Acids; D003517:Cyclopentanes
keywords: GHB; GHB binding site distribution; HOCPCA; PET; in vitro autoradiography