title: Evaluation of [¹⁸F]MK-0911, a positron emission tomography (PET) tracer for opioid receptor-like 1 (ORL1), in rhesus monkey and human.
abstract: Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity (18)F for positron emission tomography (PET) studies. Evaluation of [(18)F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [(18)F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [(18)F]MK-0911 in all gray matter regions. Baseline PET studies with [(18)F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [(18)F]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V(T)) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [(18)F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [(18)F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [(18)F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states.
authors.affiliation: Imaging, Merck Research Laboratories, West Point, PA 19486, USA. eric_hostetler@merck.com
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.forename: Sandra
authors.initials: S
authors.lastname: Sanabria-Bohórquez
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.forename: Aniket D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Shailendra
authors.initials: S
authors.lastname: Patel
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Gibson
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Malley
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Krause
authors.forename: Christine
authors.initials: C
authors.lastname: Ryan
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.forename: Sheng
authors.initials: S
authors.lastname: Bi
authors.forename: Osamu
authors.initials: O
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ozaki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
authors.forename: Tjibbe
authors.initials: T
authors.lastname: de Groot
authors.forename: Guy
authors.initials: G
authors.lastname: Bormans
authors.forename: Marleen
authors.initials: M
authors.lastname: Depré
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Inge
authors.initials: I
authors.lastname: De Lepeleire
authors.forename: Tom
authors.initials: T
authors.lastname: Reynders
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
authors.forename: Michael
authors.initials: M
authors.lastname: Egan
authors.forename: William
authors.initials: W
authors.lastname: Cho
authors.forename: Koen
authors.initials: K
authors.lastname: van Laere
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000328:Adult; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D011957:Receptors, Opioid / Q000378:metabolism*; D014018:Tissue Distribution; D055815:Young Adult; D000094942:Nociceptin Receptor
chemical_list: D001562:Benzimidazoles; D005462:Fluorine Radioisotopes; C582574:MK-0911; D010880:Piperidines; D019275:Radiopharmaceuticals; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor