Positron Emission Tomography (PET) Ligand Development for Ionotropic Glutamate Receptors: Challenges and Opportunities for Radiotracer Targeting N-Methyl-d-aspartate (NMDA), α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA), and Kainate Receptors

J Med Chem. 2019 Jan 24;62(2):403-419. doi: 10.1021/acs.jmedchem.8b00714. Epub 2018 Aug 27.

Abstract

Ionotropic glutamate receptors (iGluRs) mediate excitatory neurotransmission within the mammalian central nervous system. iGluRs exist as three main groups: N-methyl-d-aspartate receptors (NMDARs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), and kainate receptors. The past decades have witnessed a remarkable development of PET tracers targeting different iGluRs including NMDARs and AMPARs, and several of the tracers have advanced to clinical imaging studies. Here, we assess the recent development of iGluR PET probes, focusing on tracer design, brain kinetics, and performance in PET imaging studies. Furthermore, this review will not only present challenges in the tracer development but also provide novel approaches in conjunction with most recent drug discovery efforts on these iGluRs, including subtype-selective NMDAR and transmembrane AMPAR regulatory protein modulators and positive allosteric modulators (PAMs) of AMPARs. These approaches, if successful as PET tracers, may provide fundamental knowledge to understand the roles of iGluR receptors under physiological and pathological conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Central Nervous System / diagnostic imaging
  • Central Nervous System / metabolism
  • Humans
  • Ligands*
  • Positron-Emission Tomography / methods*
  • Radiopharmaceuticals / chemistry*
  • Receptors, AMPA / chemistry
  • Receptors, AMPA / metabolism
  • Receptors, Ionotropic Glutamate / chemistry*
  • Receptors, Ionotropic Glutamate / metabolism
  • Receptors, Kainic Acid / chemistry
  • Receptors, Kainic Acid / metabolism
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / metabolism

Substances

  • Ligands
  • Radiopharmaceuticals
  • Receptors, AMPA
  • Receptors, Ionotropic Glutamate
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate