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

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

Hualong Fu  1 , Zhen Chen  1 , Lee Josephson  1 , Zijing Li  2 , Steven H Liang  1
Affiliations
Review

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

Hualong Fu et al. J Med Chem. .

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.

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Figures

Figure 1.
Figure 1.
Chemical structures of selected channel blocker radiotracers.
Figure 2.
Figure 2.
Chemical structures of selected glycine site radiotracers.
Figure 3.
Figure 3.
Chemical structures of ifenprodil (17) and GluN2B-selective PET tracers (18-32).
Figure 4.
Figure 4.
Chemical structures of reported PET tracers for AMPARs (32-48 and 50) and KARs (51), and an AMPARs potentiator (49).
Figure 5.
Figure 5.
Chemical structures of reported radiotracers (52-55) and an antagonist (56) for GluN1/2A subunit, and NAMs (57-59 and 62) and PAMs (60, 61, 63 and 64) for GluN2A-2D subunits.
Figure 6.
Figure 6.
Chemical structures of TARP γ-8-dependent antagonists (65 and 66) and AMPAR PAMs (67-70).
See this image and copyright information in PMC

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