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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

Chemical structure of imaging probes for glycine binding site of NMDARs.
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Related In: Results  -  Collection


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fig3: Chemical structure of imaging probes for glycine binding site of NMDARs.

Mentions: A number of antagonists of the NMDAR glycine binding site have been developed as anticonvulsant and neuroprotective drugs [38]. Several radiolabeled cyclic amino acid derivatives, such as [11C]-3-[2-[(3-methoxyphenylamino) carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid ([11C]3MPICA, Figure 3) and [18F]2, have excellent binding affinities for the glycine binding site (Ki = 4.8 and 6.0 nM, resp.). However, they showed poor in vivo BBB permeability and had brain accumulation patterns that were inconsistent with those of the NMDAR [39, 40]. Since the low brain uptake of the cyclic amino acid derivatives was due to the highly polar charged carboxylate group, 4-hydroxyquinolones (4-HQs), which are carboxylic bioisosteres, have been investigated as high-affinity antagonists of the glycine binding site. 3-[3-(4-[11C]methoxybenzyl)phenyl]-4-hydroxy-7-chloroquinolin-2(1H)-one ([11C]L-703,717, Figure 3) has been developed as one of the most potent glycine site antagonists with a 4-HQ backbone (IC50 = 4.5 nM versus [3H]L-689,560) [41, 42]. In vivo experiments in mice showed poor initial brain uptake of [11C]L-703,717 {0.32−0.36 percent injected dose per gram of tissue (% ID/g) at 1 min} and high levels of radioactivity in the blood. Since warfarin administration caused a dose-dependent enhancement of the initial brain uptake of [11C]L-703,717, this tracer may have a high affinity for plasma protein warfarin binding sites. The accumulation of [11C]L-703,717 in the cerebrum was lower than that observed in the cerebellum at 30 min (0.20% ID/g versus 0.65% ID/g). This distribution pattern was inconsistent with that of NMDAR expression. It should be noted that treatment with nonradioactive L-703,717 (2 mg/kg) only led to a significant reduction in the accumulation of [11C]L-703,717 in the cerebellum [43]. In order to improve the BBB permeability of [11C]L-703,717, an acetyl derivative of L-703,717 ([11C]AcL703, Figure 3) was developed as a prodrug radioligand. Initial brain uptake of [11C]AcL703 at 1 min was 2-fold higher than that of [11C]L-703,717. In rat brain tissues, approximately 80% of [11C]AcL703had been metabolized to [11C]L-703,717 by 20 min after injection. In ex vivo studies, [11C]AcL703 showed higher uptake in the cerebellum than in the cerebrum, consistent with the findings using [11C]L-703,717 [44]. Although a clinical PET study of [11C]AcL703 was performed in healthy volunteers, cerebellar NMDARs could not be visualized by PET due to poor BBB penetration [45]. Other radiolabeled 4-HQs (3 and 4, Figure 3) with lower lipophilicity than [11C]L-703,717 have been developed as high-affinity radioligands for the glycine site (Ki = 7.2 and 10.3 nM). However, [11C]3 and [11C]4 did not exhibit a significant increase in brain uptake, as compared with [11C]L-703,717 [46]. The 4-HQs are acidic (pKa ≦ 5) [42] and this may result in strong binding affinity for serum albumin and low BBB penetration. Thus, several amino 4-HQ derivatives with lower pKa values were synthesized and evaluated as new PET radioligands for the glycine site. Methylamino derivatives of 4-HQs, 5 and 6 (Figure 3), showed high affinity for the glycine site (Ki = 11.7 nM and 11.8 nM, resp.). Although the amine derivatives showed a much lower plasma protein binding ratio than the methoxy analogs, [11C]6 still displayed poor uptake into the brain [47]. Further structure-activity relationship studies are necessary to develop PET ligands for the glycine site with significantly improved BBB penetration. Furthermore, the brain distribution of imaging agents interacting with the glycine site can be greatly influenced by endogenous agonists. The NMDAR coagonists, glycine and d-serine, are present in the brain at micromolar levels. Glycine is ubiquitously distributed in the brain, while d-serine is predominantly found in the forebrain [48, 49]. Levels of d-serine are reportedly very low level in the cerebellum, because of the high expression level of an enzyme (d-amino acid oxidase, DAO) that can degrade d-serine [50]. Consistent with the above reports, the [11C]L-703,717 signal in the cerebellum was diminished in mutant ddY/DAO-mice, which have high cerebellar d-serine levels (Figure 4). Therefore, the low accumulation of [11C]L-703,717 in forebrain regions may reflect the strong inhibition caused by the high level of endogenous d-serine. Similarly, the higher uptake of [11C]L-703,717 in the cerebellum might be due to reduced binding inhibition by d-serine [51].


Development of PET and SPECT probes for glutamate receptors.

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

Chemical structure of imaging probes for glycine binding site of NMDARs.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4385697&req=5

fig3: Chemical structure of imaging probes for glycine binding site of NMDARs.
Mentions: A number of antagonists of the NMDAR glycine binding site have been developed as anticonvulsant and neuroprotective drugs [38]. Several radiolabeled cyclic amino acid derivatives, such as [11C]-3-[2-[(3-methoxyphenylamino) carbonyl]ethenyl]-4,6-dichloroindole-2-carboxylic acid ([11C]3MPICA, Figure 3) and [18F]2, have excellent binding affinities for the glycine binding site (Ki = 4.8 and 6.0 nM, resp.). However, they showed poor in vivo BBB permeability and had brain accumulation patterns that were inconsistent with those of the NMDAR [39, 40]. Since the low brain uptake of the cyclic amino acid derivatives was due to the highly polar charged carboxylate group, 4-hydroxyquinolones (4-HQs), which are carboxylic bioisosteres, have been investigated as high-affinity antagonists of the glycine binding site. 3-[3-(4-[11C]methoxybenzyl)phenyl]-4-hydroxy-7-chloroquinolin-2(1H)-one ([11C]L-703,717, Figure 3) has been developed as one of the most potent glycine site antagonists with a 4-HQ backbone (IC50 = 4.5 nM versus [3H]L-689,560) [41, 42]. In vivo experiments in mice showed poor initial brain uptake of [11C]L-703,717 {0.32−0.36 percent injected dose per gram of tissue (% ID/g) at 1 min} and high levels of radioactivity in the blood. Since warfarin administration caused a dose-dependent enhancement of the initial brain uptake of [11C]L-703,717, this tracer may have a high affinity for plasma protein warfarin binding sites. The accumulation of [11C]L-703,717 in the cerebrum was lower than that observed in the cerebellum at 30 min (0.20% ID/g versus 0.65% ID/g). This distribution pattern was inconsistent with that of NMDAR expression. It should be noted that treatment with nonradioactive L-703,717 (2 mg/kg) only led to a significant reduction in the accumulation of [11C]L-703,717 in the cerebellum [43]. In order to improve the BBB permeability of [11C]L-703,717, an acetyl derivative of L-703,717 ([11C]AcL703, Figure 3) was developed as a prodrug radioligand. Initial brain uptake of [11C]AcL703 at 1 min was 2-fold higher than that of [11C]L-703,717. In rat brain tissues, approximately 80% of [11C]AcL703had been metabolized to [11C]L-703,717 by 20 min after injection. In ex vivo studies, [11C]AcL703 showed higher uptake in the cerebellum than in the cerebrum, consistent with the findings using [11C]L-703,717 [44]. Although a clinical PET study of [11C]AcL703 was performed in healthy volunteers, cerebellar NMDARs could not be visualized by PET due to poor BBB penetration [45]. Other radiolabeled 4-HQs (3 and 4, Figure 3) with lower lipophilicity than [11C]L-703,717 have been developed as high-affinity radioligands for the glycine site (Ki = 7.2 and 10.3 nM). However, [11C]3 and [11C]4 did not exhibit a significant increase in brain uptake, as compared with [11C]L-703,717 [46]. The 4-HQs are acidic (pKa ≦ 5) [42] and this may result in strong binding affinity for serum albumin and low BBB penetration. Thus, several amino 4-HQ derivatives with lower pKa values were synthesized and evaluated as new PET radioligands for the glycine site. Methylamino derivatives of 4-HQs, 5 and 6 (Figure 3), showed high affinity for the glycine site (Ki = 11.7 nM and 11.8 nM, resp.). Although the amine derivatives showed a much lower plasma protein binding ratio than the methoxy analogs, [11C]6 still displayed poor uptake into the brain [47]. Further structure-activity relationship studies are necessary to develop PET ligands for the glycine site with significantly improved BBB penetration. Furthermore, the brain distribution of imaging agents interacting with the glycine site can be greatly influenced by endogenous agonists. The NMDAR coagonists, glycine and d-serine, are present in the brain at micromolar levels. Glycine is ubiquitously distributed in the brain, while d-serine is predominantly found in the forebrain [48, 49]. Levels of d-serine are reportedly very low level in the cerebellum, because of the high expression level of an enzyme (d-amino acid oxidase, DAO) that can degrade d-serine [50]. Consistent with the above reports, the [11C]L-703,717 signal in the cerebellum was diminished in mutant ddY/DAO-mice, which have high cerebellar d-serine levels (Figure 4). Therefore, the low accumulation of [11C]L-703,717 in forebrain regions may reflect the strong inhibition caused by the high level of endogenous d-serine. Similarly, the higher uptake of [11C]L-703,717 in the cerebellum might be due to reduced binding inhibition by d-serine [51].

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