Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1 H-3-benzazepine and 6,7,8,9-Tetrahydro-5 H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1 H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-d-aspartate Receptors

J Med Chem. 2019 Nov 14;62(21):9450-9470. doi: 10.1021/acs.jmedchem.9b00812. Epub 2019 Oct 28.

Abstract

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [18F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [18F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [18F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemistry*
  • Amines / metabolism*
  • Amines / pharmacokinetics
  • Animals
  • Benzazepines / chemistry*
  • Benzazepines / metabolism*
  • Benzazepines / pharmacokinetics
  • Halogenation*
  • Male
  • Positron-Emission Tomography / methods*
  • Protein Binding
  • Radiography
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Structure-Activity Relationship

Substances

  • Amines
  • Benzazepines
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate