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Development of PET and SPECT probes for glutamate receptors.

Fuchigami T, Nakayama M, Yoshida S - ScientificWorldJournal (2015)

Bottom Line: L-glutamate and its receptors (GluRs) play a key role in excitatory neurotransmission within the mammalian central nervous system (CNS).GluRs are classified into two major groups: ionotropic GluRs (iGluRs), which are ligand-gated ion channels, and metabotropic GluRs (mGluRs), which are coupled to heterotrimeric guanosine nucleotide binding proteins (G-proteins).Although no satisfactory imaging agents have yet been developed for iGluRs, several PET ligands for mGluRs have been successfully employed in clinical studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.

ABSTRACT
L-glutamate and its receptors (GluRs) play a key role in excitatory neurotransmission within the mammalian central nervous system (CNS). Impaired regulation of GluRs has also been implicated in various neurological disorders. GluRs are classified into two major groups: ionotropic GluRs (iGluRs), which are ligand-gated ion channels, and metabotropic GluRs (mGluRs), which are coupled to heterotrimeric guanosine nucleotide binding proteins (G-proteins). Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of GluRs could provide a novel view of CNS function and of a range of brain disorders, potentially leading to the development of new drug therapies. Although no satisfactory imaging agents have yet been developed for iGluRs, several PET ligands for mGluRs have been successfully employed in clinical studies. This paper reviews current progress towards the development of PET and SPECT probes for GluRs.

No MeSH data available.


Related in: MedlinePlus

In vitro autoradiogram of [11C]7 (a) and quantified values of the autoradiogram in frontal cortex (FTX), hippocampus (HIP), striatum (STR), thalamus (THA), and cerebellum (CB) (b). Nonspecific binding was determined in the presence of (+) CP-101,606 (10 μM). (c) Time radioactivity curves in the monkey brain after administration of [11C]7. Nonradioactive 7 (2 mg/kg) was coinjected with [11C]7 into the same monkey [55].
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fig6: In vitro autoradiogram of [11C]7 (a) and quantified values of the autoradiogram in frontal cortex (FTX), hippocampus (HIP), striatum (STR), thalamus (THA), and cerebellum (CB) (b). Nonspecific binding was determined in the presence of (+) CP-101,606 (10 μM). (c) Time radioactivity curves in the monkey brain after administration of [11C]7. Nonradioactive 7 (2 mg/kg) was coinjected with [11C]7 into the same monkey [55].

Mentions: NMDARs containing the NR2B subunit play a key role in various diseases, such as Parkinson's disease, Alzheimer's disease, and neuropathic pain. NR2B negative modulators have been developed for the treatment of these conditions [17, 52]. Ligands targeting NR2B, including ifenprodil, are thought to bind at the interlobe cleft of the NR2B subunit [53]. CP-101,606 is a potent NMDAR antagonist that is highly selective for NR2B subunit-containing receptors, with Kd values of 10 nM [54]. Because CP-101,606 was identified as a potent NR2B negative modulator (Ki = 10 nM), a 11C-labeled CP-101,606 derivative ([11C]7, Figure 5) was developed as a PET ligand for the NR2B subunit [55]. In vitro binding of [11C]7 in rat brain slices was extremely high in the forebrain regions and very low in the cerebellum, with excellent specific binding (Figures 6(a) and 6(b)). This distribution pattern matched the NR2B subunit expression pattern [56]. However, in vivo studies in mice and monkeys demonstrated that this tracer showed homogeneous brain distribution and no specific binding of [11C]7 was observed (Figure 6(c)) [55]. A benzylpiperidine derivative, [11C]8 (Figure 5), has been developed as a selective high-affinity PET ligand for NR2B-containing NMDARs (IC50 = 5.3 nM). An in vivo study in rats showed poor brain uptake of [11C]8 and a localization that was inconsistent with the NR2B expression pattern [57]. [11C]EMD-95885 (Figure 5), a benzylpiperidine derivative with a high affinity for NR2B (IC50 = 3.9 nM), has been synthesized and evaluated. In vivo experiments in rats showed 59-fold higher brain uptake of [11C]EMD-95885 than of [11C]8. Although [11C]EMD-95885 displayed homogeneous binding in brain tissues, a substantial reduction in brain uptake of [11C]EMD-95885 was observed in the presence of nonradioactive 8 or ifenprodil, suggesting that some specific binding may occur in the brain. However, these blocking effects were observed in both NR2B-rich and NR2B-poor regions [58]. The benzimidazole derivatives, 9 and 10 (Figure 5), have been identified as having high affinity for the NR2B subunit, with Ki values of 7.3 nM and 5.8 nM, respectively. Both [125I]9 and [125I]10 showed localizations consistent with NR2B subunit expression in rat brain slices. In vivo studies in mice found moderate brain uptake of [125I]9 and [125I]10 and distribution that was inconsistent with known NR2B expression patterns. However, treatment with nonradioactive 9 or the NR2B ligand, [(±)-(R*,  S*)]-a-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25–6981), caused 34% and 59% reduction in the brain/blood ratio of [125I]9, respectively. This tracer may therefore show partially specific binding to the NR2B subunit in vivo [59]. Further structural modification of 9 may contribute to the development of more promising imaging probes for the NR2B subunit. [2-(3,4-Dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]–[11C]dimethylamine ([11C]Ro-647312, Figure 5) has been evaluated as a member of a different class of PET ligands with high affinity for the NR2B subunit (Ki = 8.0 nM). However, in vivo biodistribution of [11C]Ro-647312 was almost homogeneous in the brain [60]. Several benzylamidines, such as [11C]11 (Figure 5), have been developed as high-affinity PET ligands for NR2B (Ki = 5.7 nM for 11). In vitro, [11C]11 showed excellent specific binding and a similar localization to that of NR2B. However, [11C]11 is an unsuitable imaging agent due to metabolic instability [61]. (3S,4R)-4-Methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino) methyl) piperidine-1-carboxylate (MK-0657) was developed as a highly potent NR2B antagonist (IC50 = 3.6 nM) for the treatment of neuropathic pain, Parkinson's disease, and major depression [17, 62]. Two radiofluorinated diastereoisomers of MK-0657 ([18F]trans-MK-0657 and [18F]cis-MK-0657, Figure 5) exhibited a localization pattern consistent with that of NR2B expression and very high specific binding for the NR2B modulator binding site. However, no further in vivo evaluations of these potential imaging agents have been reported [63].


Development of PET and SPECT probes for glutamate receptors.

Fuchigami T, Nakayama M, Yoshida S - ScientificWorldJournal (2015)

In vitro autoradiogram of [11C]7 (a) and quantified values of the autoradiogram in frontal cortex (FTX), hippocampus (HIP), striatum (STR), thalamus (THA), and cerebellum (CB) (b). Nonspecific binding was determined in the presence of (+) CP-101,606 (10 μM). (c) Time radioactivity curves in the monkey brain after administration of [11C]7. Nonradioactive 7 (2 mg/kg) was coinjected with [11C]7 into the same monkey [55].
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig6: In vitro autoradiogram of [11C]7 (a) and quantified values of the autoradiogram in frontal cortex (FTX), hippocampus (HIP), striatum (STR), thalamus (THA), and cerebellum (CB) (b). Nonspecific binding was determined in the presence of (+) CP-101,606 (10 μM). (c) Time radioactivity curves in the monkey brain after administration of [11C]7. Nonradioactive 7 (2 mg/kg) was coinjected with [11C]7 into the same monkey [55].
Mentions: NMDARs containing the NR2B subunit play a key role in various diseases, such as Parkinson's disease, Alzheimer's disease, and neuropathic pain. NR2B negative modulators have been developed for the treatment of these conditions [17, 52]. Ligands targeting NR2B, including ifenprodil, are thought to bind at the interlobe cleft of the NR2B subunit [53]. CP-101,606 is a potent NMDAR antagonist that is highly selective for NR2B subunit-containing receptors, with Kd values of 10 nM [54]. Because CP-101,606 was identified as a potent NR2B negative modulator (Ki = 10 nM), a 11C-labeled CP-101,606 derivative ([11C]7, Figure 5) was developed as a PET ligand for the NR2B subunit [55]. In vitro binding of [11C]7 in rat brain slices was extremely high in the forebrain regions and very low in the cerebellum, with excellent specific binding (Figures 6(a) and 6(b)). This distribution pattern matched the NR2B subunit expression pattern [56]. However, in vivo studies in mice and monkeys demonstrated that this tracer showed homogeneous brain distribution and no specific binding of [11C]7 was observed (Figure 6(c)) [55]. A benzylpiperidine derivative, [11C]8 (Figure 5), has been developed as a selective high-affinity PET ligand for NR2B-containing NMDARs (IC50 = 5.3 nM). An in vivo study in rats showed poor brain uptake of [11C]8 and a localization that was inconsistent with the NR2B expression pattern [57]. [11C]EMD-95885 (Figure 5), a benzylpiperidine derivative with a high affinity for NR2B (IC50 = 3.9 nM), has been synthesized and evaluated. In vivo experiments in rats showed 59-fold higher brain uptake of [11C]EMD-95885 than of [11C]8. Although [11C]EMD-95885 displayed homogeneous binding in brain tissues, a substantial reduction in brain uptake of [11C]EMD-95885 was observed in the presence of nonradioactive 8 or ifenprodil, suggesting that some specific binding may occur in the brain. However, these blocking effects were observed in both NR2B-rich and NR2B-poor regions [58]. The benzimidazole derivatives, 9 and 10 (Figure 5), have been identified as having high affinity for the NR2B subunit, with Ki values of 7.3 nM and 5.8 nM, respectively. Both [125I]9 and [125I]10 showed localizations consistent with NR2B subunit expression in rat brain slices. In vivo studies in mice found moderate brain uptake of [125I]9 and [125I]10 and distribution that was inconsistent with known NR2B expression patterns. However, treatment with nonradioactive 9 or the NR2B ligand, [(±)-(R*,  S*)]-a-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro 25–6981), caused 34% and 59% reduction in the brain/blood ratio of [125I]9, respectively. This tracer may therefore show partially specific binding to the NR2B subunit in vivo [59]. Further structural modification of 9 may contribute to the development of more promising imaging probes for the NR2B subunit. [2-(3,4-Dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]–[11C]dimethylamine ([11C]Ro-647312, Figure 5) has been evaluated as a member of a different class of PET ligands with high affinity for the NR2B subunit (Ki = 8.0 nM). However, in vivo biodistribution of [11C]Ro-647312 was almost homogeneous in the brain [60]. Several benzylamidines, such as [11C]11 (Figure 5), have been developed as high-affinity PET ligands for NR2B (Ki = 5.7 nM for 11). In vitro, [11C]11 showed excellent specific binding and a similar localization to that of NR2B. However, [11C]11 is an unsuitable imaging agent due to metabolic instability [61]. (3S,4R)-4-Methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino) methyl) piperidine-1-carboxylate (MK-0657) was developed as a highly potent NR2B antagonist (IC50 = 3.6 nM) for the treatment of neuropathic pain, Parkinson's disease, and major depression [17, 62]. Two radiofluorinated diastereoisomers of MK-0657 ([18F]trans-MK-0657 and [18F]cis-MK-0657, Figure 5) exhibited a localization pattern consistent with that of NR2B expression and very high specific binding for the NR2B modulator binding site. However, no further in vivo evaluations of these potential imaging agents have been reported [63].

Bottom Line: L-glutamate and its receptors (GluRs) play a key role in excitatory neurotransmission within the mammalian central nervous system (CNS).GluRs are classified into two major groups: ionotropic GluRs (iGluRs), which are ligand-gated ion channels, and metabotropic GluRs (mGluRs), which are coupled to heterotrimeric guanosine nucleotide binding proteins (G-proteins).Although no satisfactory imaging agents have yet been developed for iGluRs, several PET ligands for mGluRs have been successfully employed in clinical studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Hygienic Chemistry, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan.

ABSTRACT
L-glutamate and its receptors (GluRs) play a key role in excitatory neurotransmission within the mammalian central nervous system (CNS). Impaired regulation of GluRs has also been implicated in various neurological disorders. GluRs are classified into two major groups: ionotropic GluRs (iGluRs), which are ligand-gated ion channels, and metabotropic GluRs (mGluRs), which are coupled to heterotrimeric guanosine nucleotide binding proteins (G-proteins). Positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of GluRs could provide a novel view of CNS function and of a range of brain disorders, potentially leading to the development of new drug therapies. Although no satisfactory imaging agents have yet been developed for iGluRs, several PET ligands for mGluRs have been successfully employed in clinical studies. This paper reviews current progress towards the development of PET and SPECT probes for GluRs.

No MeSH data available.


Related in: MedlinePlus