title: Discovery of [¹¹C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.
abstract: Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. Electronic address: chris_cox@merck.com.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Broc A
authors.initials: BA
authors.lastname: Flores
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Fan
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Gantert
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Aniket
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Chemical Modeling & Informatics, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: McGaughey
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Meng
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Purcell
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Izzat T
authors.initials: IT
authors.lastname: Raheem
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.affiliation: Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.affiliation: Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Discovery Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry*; D008253:Macaca mulatta; D008958:Models, Molecular; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000097:blood / Q000378:metabolism*; D049268:Positron-Emission Tomography; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002250:Carbon Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring; C000608315:MK-8193; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases
keywords: Huntington’s disease; Imaging; PDE10A; PET tracer; Phosphodiesterase 10A; Positron emission tomography; Schizophrenia