title: Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18)F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs).
abstract: Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.
authors.affiliation: Discovery Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Abbas M
authors.initials: AM
authors.lastname: Walji
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hostetler
authors.affiliation: Discovery Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Harold
authors.initials: H
authors.lastname: Selnick
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Miller
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Idriss
authors.initials: I
authors.lastname: Bennacef
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Brett
authors.initials: B
authors.lastname: Connolly
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Liza
authors.initials: L
authors.lastname: Gantert
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Marie
authors.initials: M
authors.lastname: Holahan
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: O'Malley
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Mona
authors.initials: M
authors.lastname: Purcell
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.affiliation: Process Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Process Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Jaume
authors.initials: J
authors.lastname: Balsells
authors.affiliation: Pharmacology, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Julie A
authors.initials: JA
authors.lastname: OBrien
authors.affiliation: Pharmacology, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Stacey
authors.initials: S
authors.lastname: Melquist
authors.affiliation: Pharmacology, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Aileen
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Pharmacology, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Pharmacology, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Aimie
authors.initials: A
authors.lastname: Ogawa
authors.affiliation: Pharmacology, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
authors.forename: Serena
authors.initials: S
authors.lastname: Xu
authors.affiliation: Drug Metabolism, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Joshi
authors.affiliation: Discovery Pharmaceutical Sciences, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Della Rocca
authors.affiliation: Neuroscience, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Hess
authors.affiliation: Neuroscience, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Schachter
authors.affiliation: Labelled Compound Synthesis, Merck & Co., Inc. , Rahway, New Jersey, 07065, United States.
authors.forename: David
authors.initials: D
authors.lastname: Hesk
authors.affiliation: Labelled Compound Synthesis, Merck & Co., Inc. , Rahway, New Jersey, 07065, United States.
authors.forename: David
authors.initials: D
authors.lastname: Schenk
authors.affiliation: Clinical Pharmacology, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Arie
authors.initials: A
authors.lastname: Struyk
authors.affiliation: Computational Chemistry, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
authors.forename: Kerim
authors.initials: K
authors.lastname: Babaoglu
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Talakad G
authors.initials: TG
authors.lastname: Lohith
authors.affiliation: Pharmaron Beijing Co., Ltd. , Beijing 100176, China.
authors.forename: Yaode
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Pharmaron Beijing Co., Ltd. , Beijing 100176, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.affiliation: Pharmaron Beijing Co., Ltd. , Beijing 100176, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fu
authors.affiliation: Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Evelhoch
authors.affiliation: Discovery Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D055808:Drug Discovery; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D057054:Molecular Imaging; D015394:Molecular Structure; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography
chemical_list: D005462:Fluorine Radioisotopes; D007546:Isoquinolines; C000618291:MK-6240