title: Synthesis and Pharmacological Evaluation of Identified and Putative Metabolites of the A1Adenosine Receptor Antagonist 8-Cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine (CPFPX).
abstract: The A1adenosine receptor (A1AR) antagonist [18F]8-cyclopentyl-3-(3-fluoropropyl)-1-propylxanthine ([18F]CPFPX), used in imaging human brain A1ARs by positron emission tomography (PET), is stable in the brain, but rapidly undergoes transformation into one major (3-(3-fluoropropyl)-8-(3-oxocyclopenten-1-yl)-1-propylxanthine, M1) and several minor metabolites in blood. This report describes the synthesis of putative metabolites of CPFPX as standards for the identification of those metabolites. Analysis by (radio)HPLC revealed that extracts of human liver microsomes incubated with no-carrier-added (n.c.a.)[18F]CPFPX contain the major metabolite, M1, as well as radioactive metabolites corresponding to derivatives functionalized at the cyclopentyl moiety, but no N1-despropyl species or metabolites resulting from functionalization of the N3-fluoropropyl chain. The putative metabolites were found to displace the binding of [3H]CPFPX to the A1AR in pig brain cortex at Kivalues between 1.9 and 380 nm and the binding of [3H]ZM241385 to the A2AAR in pig striatum at Kivalues >180 nm. One metabolite, a derivative functionalized at the ω-position of the N1-propyl chain, showed high affinity (Ki2 nm) to and very good selectivity (>9000) for the A1AR.
authors.affiliation: Institut für Neurowissenschaften und Medizin-Nuklearchemie, INM-5, Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428, Jülich, Germany.
authors.forename: Marcus H
authors.initials: MH
authors.lastname: Holschbach
authors.affiliation: Institut für Neurowissenschaften und Medizin-Nuklearchemie, INM-5, Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428, Jülich, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Bier
authors.affiliation: Institut für Radiopharmazeutische Krebsforschung, Helmholtz-Zentrum Dresden-Rossendorf, Bautzener Landstraße 400, 01328, Dresden, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sihver
authors.affiliation: Institut für Neurowissenschaften und Medizin-Nuklearchemie, INM-5, Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428, Jülich, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schulze
authors.affiliation: Institut für Neurowissenschaften und Medizin-Nuklearchemie, INM-5, Forschungszentrum Jülich GmbH, Wilhelm-Johnen-Straße, 52428, Jülich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Neumaier
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: C468796:8-cyclopenta-3-(3-fluoropropyl)-1-propylxanthine; D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D014970:Xanthines
keywords: A1 adenosine receptors; [18F]CPFPX; binding properties; in vitro metabolism; ligand design