title: Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.
abstract: We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hamill
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Chioda
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Harry
authors.initials: H
authors.lastname: Chobanian
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Selena
authors.initials: S
authors.lastname: Fung
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Raman
authors.initials: R
authors.lastname: Bakshi
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Qingmei
authors.initials: Q
authors.lastname: Hong
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: James
authors.initials: J
authors.lastname: Dellureficio
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Abbadie
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Alexander
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Mandala
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Shiao
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Wenping
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sanabria
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hajdu
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Nina
authors.initials: N
authors.lastname: Jochnowitz
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Rosenbach
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Bindhu
authors.initials: B
authors.lastname: Karanam
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Madeira
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Powell
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Terebetski
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Leone
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miller
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Jacquelynn
authors.initials: J
authors.lastname: Cook
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Aniket
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Malley
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Mona
authors.initials: M
authors.lastname: Purcell
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Posavec
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Tsing-Bau
authors.initials: TB
authors.lastname: Chen
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Mangay
authors.initials: M
authors.lastname: Williams
authors.affiliation: Department of Imaging Research, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Sullivan
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Ravi P
authors.initials: RP
authors.lastname: Nargund
authors.affiliation: Departments of Medicinal Chemistry, Immunology, Pharmacology, Preclinical DMPK, Basic Pharmaceutical Sciences, and Process Research, Merck Research Laboratories , Rahway, New Jersey 07065, United States.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: DeVita
keywords: FAAH; Fatty acid amide hydrolase; PET tracer; biomarker; carbon-11; positron emission tomography; target engagement