Discovery of N-(4-[18F]Fluoro-5-methylpyridin-2-yl)isoquinolin-6-amine (JNJ-64326067), a New Promising Tau Positron Emission Tomography Imaging Tracer

  • J Med Chem. 2019 Mar 28;62(6):2974-2987. doi: 10.1021/acs.jmedchem.8b01759.
Frederik J R Rombouts  1 ,  Lieven Declercq ,  José-Ignacio Andrés  2 ,  Astrid Bottelbergs  1 ,  Lu Chen  3 ,  Laura Iturrino  2 ,  Joseph E Leenaerts  1 ,  Jonas Mariën  1 ,  Fengbin Song  3 ,  Cindy Wintmolders  1 ,  Stijn Wuyts  1 ,  Chunfang A Xia  4 ,  Paula Te Riele  1 ,  Guy Bormans ,  Rik Vandenberghe ,  Hartmuth Kolb  4 ,  Diederik Moechars  1
Affiliations
  • 1. Janssen Research & Development, Janssen Pharmaceutica N. V. , Turnhoutseweg 30 , B-2340 Beerse , Belgium.
  • 2. Janssen Research & Development, Janssen-Cilag S. A. , C/Jarama 75A , 45007 Toledo , Spain.
  • 3. Janssen Research & Development , Welsh & McKean Roads , Spring House , Pennsylvania 19477 , United States.
  • 4. Janssen Research & Development , 3210 Merryfield Row , San Diego , California 92121 , United States.
PMID: 30810314 DOI: 10.1021/acs.jmedchem.8b01759
Abstract

In Alzheimer's disease, the density and spread of aggregated Tau Protein track well with neurodegeneration and cognitive decline, making the imaging of aggregated tau a compelling biomarker. A structure-activity relationship exploration around an isoquinoline hit, followed by an exploration of tolerated fluorination positions, allowed us to identify 9 (JNJ-64326067), a potent and selective binder to aggregated tau with a favorable pharmacokinetic profile and no apparent off-target binding. This was confirmed in rat and monkey positron emission tomography studies using [18F]9.

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