2. Academic Validation
  3. 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)

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)

  • J Med Chem. 2016 May 26;59(10):4778-89. doi: 10.1021/acs.jmedchem.6b00166.
Abbas M Walji 1,  Eric D Hostetler 2,  Harold Selnick 1,  Zhizhen Zeng 2,  Patricia Miller 2,  Idriss Bennacef 2,  Cristian Salinas 2,  Brett Connolly 2,  Liza Gantert 2,  Marie Holahan 2,  Stacey O'Malley 2,  Mona Purcell 2,  Kerry Riffel 2,  Jing Li 3,  Jaume Balsells 3,  Julie A OBrien 4,  Stacey Melquist 4,  Aileen Soriano 5,  Xiaoping Zhang 5,  Aimie Ogawa 5,  Serena Xu 5,  Elizabeth Joshi 6,  Joseph Della Rocca 7,  Fred J Hess 8,  Joel Schachter 8,  David Hesk 9,  David Schenk 9,  Arie Struyk 10,  Kerim Babaoglu 11,  Talakad G Lohith 2,  Yaode Wang 12,  Kun Yang 12,  Jianmin Fu 12,  Jeffrey L Evelhoch 2,  Paul J Coleman 1
Affiliations

Affiliations

  • 1 Discovery Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
  • 2 Imaging, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
  • 3 Process Chemistry, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
  • 4 Pharmacology, Merck & Co., Inc. , West Point Pennsylvania 19486, United States.
  • 5 Pharmacology, Merck & Co., Inc. , Kenilworth, New Jersey 07033, United States.
  • 6 Drug Metabolism, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
  • 7 Discovery Pharmaceutical Sciences, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
  • 8 Neuroscience, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
  • 9 Labelled Compound Synthesis, Merck & Co., Inc. , Rahway, New Jersey, 07065, United States.
  • 10 Clinical Pharmacology, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
  • 11 Computational Chemistry, Merck & Co., Inc. , West Point, Pennsylvania 19486, United States.
  • 12 Pharmaron Beijing Co., Ltd. , Beijing 100176, China.
PMID: 27088900 DOI: 10.1021/acs.jmedchem.6b00166
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.

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