A Review of Molecular Imaging of Glutamate Receptors

Abstract

Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

Keywords: glutamate receptors; positron emission tomography; radioligands; single photon emission computed tomography.

Figure 1

Chemical structures of excitatory amino acids (EAAs), sulfur-containing amino acids (SCAAs), and polyamines.

Figure 2

Chemical structures of some prototypic N-methyl-d-aspartate (NMDA) receptor ligands.

Figure 3

Chemical structures of labelled NMDA receptor ligands developed for the MK801/phencyclidine (PCP)-binding site of the NMDA ion channel.

Figure 4

Structure of selected radioligands for the GluN2B subunit of NMDA receptors.

Figure 5

Structures of radiotracers for the glycine-binding site of the NMDA receptor.

Figure 6

Structures of selected AMPA receptor ligands and non-competitive AMPA antagonists with 2,3-benzodiazepine scaffold.

Figure 7

Structures of selected metabotropic glutamate receptor radiotracers (Group I, mGluR1).

Figure 8

Structures of radiotracers for metabotropic glutamate receptors (Group I, mGluR5).

Figure 9

Representative mean images of [¹¹C]ABP688 PET and corresponding MRI in a group of 23 healthy human subjects (Courtesy of the Neuroscience Research Institute, Gachon University, Incheon, South Korea).

Figure 10

Structures of radiotracers for Group II (mGluR2 and mGluR3) and Group III (mGluR 4, 6, 7 and 8).