title: Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [(11)C]MK-8193.
abstract: A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [(11)C]MK-8193 is described.
  
  
  
  In vitro binding studies with [(3)H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [(11)C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor.
  
  
  
  [(3)H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [(11)C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships.
  
  
  
  [(11)C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [(11)C]MK-8193 in humans is warranted.
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA. eric.hostetler@merck.com.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Fan
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Aniket D
authors.initials: AD
authors.lastname: Joshi
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Liza
authors.initials: L
authors.lastname: Gantert
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Meng
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miller
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Malley
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Purcell
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Mangay
authors.initials: M
authors.lastname: Williams
authors.affiliation: Drug Metabolism, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Bennett
authors.initials: B
authors.lastname: Ma
authors.affiliation: Pharmaceutical Sciences, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Buist
authors.affiliation: Neuroscience, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Smith
authors.affiliation: Discovery Chemistry, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Discovery Chemistry, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Cox
authors.affiliation: Discovery Chemistry, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Brock A
authors.initials: BA
authors.lastname: Flores
authors.affiliation: Discovery Chemistry, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Izzat T
authors.initials: IT
authors.lastname: Raheem
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.affiliation: Imaging, Merck & Co., Inc, West Point, PA, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D006574:Heterocyclic Compounds, 2-Ring; C000608315:MK-8193; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases
keywords: Carbon-11; Enzyme; Imaging; Monkey; Occupancy; PDE10A; PET; Phosphodiesterase 10A; Rat