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A Review of Molecular Imaging of Glutamate Receptors

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A Review of Molecular Imaging of Glutamate Receptors molecules Review A Review of Molecular Imaging of Glutamate Receptors Jong-Hoon Kim 1,2,3,* ,János Marton 4, Simon Mensah Ametamey 5 and Paul Cumming 6,7,* 1 Neuroscience Research Institute, Gachon University, Incheon 21565, Korea 2 Gachon Advanced Institute for Health Science and Technology, Graduate School, Incheon 21565, Korea 3 Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Gachon University, Incheon 21565, Korea 4 ABX Advanced Biochemical Compounds, Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, D-1454 Radeberg, Germany; [email protected] 5 Centre for Radiopharmaceutical Sciences ETH-PSI-USZ, Institute of Pharmaceutical Sciences ETH, Vladimir-Prelog-Weg 4, CH-8093 Zürich, Switzerland; [email protected] 6 Department of Nuclear Medicine, University of Bern, Inselspital, Freiburgstrasse 18, CH-3010 Bern, Switzerland 7 School of Psychology and Counselling, Queensland University of Technology, Brisbane QLD 4059, Australia * Correspondence: [email protected] (J.-H.K.); [email protected] (P.C.); Tel.: +41-31-664-0498 (P.C.); Fax: +41-31-632-7663 (P.C.) Academic Editors: Diego Muñoz-Torrero and Beatriz De Pascual-Teresa Received: 24 September 2020; Accepted: 14 October 2020; Published: 16 October 2020 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. Molecules 2020, 25, 4749; doi:10.3390/molecules25204749 www.mdpi.com/journal/molecules Molecules 20202020,, 2525,, 4749x 2 of 4240 Keywords: glutamate receptors; positron emission tomography; single photon emission computed Keywords:tomography;glutamate radioligands receptors; positron emission tomography; single photon emission computed tomography; radioligands 1. Introduction 1. Introduction The first identification of the amino acid glutamate/glutamic acid (1) as a neurotransmitter was in theThe insect first nervous identification system of [1,2]. the amino Glutamate acid glutamateoccurs at /aglutamic concentration acid (1 of) as approximately a neurotransmitter 10 mM was in inmammalian the insect brain nervous [3], system making [1 it,2 ].the Glutamate most abund occursant amino at a concentration acid, which ofreflects approximately its presence 10 both mM in mammalianmetabolic and brain neurotransmitter [3], making it pools the most [4]. abundantPerhaps in amino keeping acid, with which its ancient reflects evolutionary its presence bothlineage in metabolicas a neurotransmitter, and neurotransmitter glutamate pools possesses [4]. Perhaps a wide in keeping variety with of receptors, its ancient evolutionarywhich have lineageabundant as aexpression neurotransmitter, on neurons glutamate and glia. possesses The glutamate a wide variety receptors of receptors,fall into two which broad have categories, abundant namely expression the onionotropic neurons receptors, and glia. which The glutamate are ligand receptors-gated ion fall channels, into two and broad the metabotropic categories, namely receptors the ionotropic(mGluRs), receptors,which have which coupling are ligand-gated to intracellular ion second channels, messenger and the metabotropicsystems. The receptorsmGluRs have (mGluRs), further which subtypes, have couplingnamely the to intracellularexcitatory type second I receptors messenger (mGluR1/mGluR5), systems. The mGluRs the adenylate have further cyclase subtypes,-inhibiting namely type the II excitatoryreceptors (mGluR2, type I receptors mGluR3), (mGluR1 and the/ mGluR5),type III receptors the adenylate (mGluR4, cyclase-inhibiting mGluR6, mGluR7, type mGluR8). II receptors The (mGluR2,ionotropic mGluR3), glutamate and receptors, the type which III receptors are designated (mGluR4, according mGluR6, to mGluR7,their excitatory mGluR8). amino The acid ionotropic ligands glutamate(Figure 1.), receptors, i.e., N-methyl which- areD-aspartate designated (NMDA, according 3), to kainate their excitatory (4), and amino AMPA acid (5 ligands)/quisqualate (Figure 1(6),) i.e.,receptors,N-methyl- are Dligand-aspartate gated (NMDA, ion channels3), kainate permissive (4), and to AMPA cation (5flux)/quisqualate across the ( 6cell) receptors, membrane. are ligandGiven gatedthis enormously ion channels diverse permissive pharmacology, to cation flux no across particular the cell membrane.or singular Givenaction this can enormously be attributed diverse to pharmacology,glutamate receptors no particular the nervous or singular system. action In general, can be however, attributed the to ionotropic glutamate receptors receptors mediate the nervous fast system.excitatory In synaptic general, however,signaling theand ionotropic have a key receptors role in mediate synaptic fast plas excitatoryticity, although synaptic their signaling excessive and haveactivation a key provokes role in synapticexcitotoxicity, plasticity, whereas although the mGluRs their excessive are modulators/shapers activation provokes of neuronal excitotoxicity, activity whereasvia their theeffects mGluRs on intracellular are modulators cyclic/shapers adenosine of neuronal monophosphate activity via ( theircAMP eff)ects levels on intracellularand other second cyclic adenosinemessengers. monophosphate (cAMP) levels and other second messengers. O CH2 O O O O H3C OH HO HO 4 3 OH HO OH OH 5 2 1 O NH O NH O HN N 2 2 CH 3 H OH 1 2 3 4 L-glutamic acid L-aspartic acid N-methyl-D-aspartic acid (2S,3S,4S)-kainic acid HO O O O O O HO HO N OH N OH HN S OH S OH O NH O O O NH2 2 NH2 O NH2 O 5 6 7 8 (S)-AMPA (2S)-quisqualic acid L-cysteic acid L-cysteine sulfinic acid O O O O O H S S N NH2 OH HO OH H2N N HO H NH2 NH2 9 10 11 L-homocysteic acid L-homocysteine sulfinic acid spermine O O H HN N NH2 H2N H2N OH O NH2 12 13 14 spermidine glycine D-cycloserine Figure 1.1.Chemical Chemical structures structures of excitatoryof excitatory amino amino acids (EAAs),acids (EAAs), sulfur-containing sulfur-containing amino acids amino (SCAAs), acids and(SCAAs) polyamines., and polyamines. There are various reviews of the pharmacology of ionotropic [5,6] and metabotropic glutamate receptors [7,8]. There is also a burgeoning literature on the involvement of glutamate receptors in the Molecules 2020, 25, 4749 3 of 42 There are various reviews of the pharmacology of ionotropic [5,6] and metabotropic glutamate receptors [7,8]. There is also a burgeoning literature on the involvement of glutamate receptors in the pathophysiology and therapeutics of Alzheimer’s dementia [9], Parkinson’s disease [10], ischemic stroke [11], epilepsy [12], autoimmune diseases of the nervous system [13], and neuropsychiatric disorders such as schizophrenia [14–16], depression [17,18], and substance abuse/addiction [19]. As such, the glutamate receptors present a diverse range of important targets for molecular brain imaging by single photon emission computed tomography (SPECT) and positron emission tomography (PET). While there have been several reviews of this topic in recent years [20–23], we now present a systematic review of the state of development of glutamate receptor imaging, placing our emphasis on the findings of clinical studies, and on
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