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. Epub 2019 Mar 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / metabolism
  • Animals
  • Cells, Cultured
  • Drug Discovery*
  • Female
  • Fluorine Radioisotopes / chemistry
  • Fluorine Radioisotopes / metabolism*
  • Fluorine Radioisotopes / pharmacokinetics
  • Hepatocytes / metabolism
  • Humans
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacokinetics*
  • Macaca mulatta
  • Male
  • Positron-Emission Tomography*
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics*
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • tau Proteins / metabolism*

Substances

  • Fluorine Radioisotopes
  • Isoquinolines
  • JNJ-64326067
  • MAPT protein, human
  • Pyridines
  • tau Proteins