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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 mGluR1.
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig7: Chemical structure of imaging probes for mGluR1.

Mentions: (3-Ethyl-2-[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl)methanone ([11C]JNJ-16567083, Figure 7) has been developed as a high-affinity, selective mGluR1 ligand (Ki = 4.41 nM for rat mGluR1, 13.3 nM for human mGluR1) [74]. Ex vivo studies using this ligand showed good brain uptake and a localization pattern consistent with mGluR1 expression. In addition, over 80% of the accumulation of [11C]JNJ-16567083 in the cerebellum was blocked by selective mGluR1 antagonists, while treatment with a selective mGluR5 antagonist produced no marked inhibition of its binding, indicating selectivity for mGluR1. In PET studies, it showed high specific binding in regions expressing mGluR1, indicating that [11C]JNJ-16567083 is bound to mGluR1 in the living rat brain [74]. An 18F-labeled JNJ-16567083 derivative ([18F]12, Figure 7) was also reported to have a high affinity for mGluR1 (Ki = 1.77 nM for rat mGluR1 and 24.4 nM for human mGluR1). The in vivo localization of [18F]12 in rats was similar to that of [11C]JNJ-16567083. The in vivo accumulation of [18F]12 in the cerebellum was inhibited by pretreatment with a selective mGluR1 antagonist, but not by an mGluR2 antagonist (LY341495) or an mGluR5 antagonist (MPEP), indicating selectivity for mGluR1 in the living rat brain. However, PET studies in baboons found that [11C]JNJ-16567083 and [18F]12 produced low brain signals, probably due to a lower receptor density in baboon brain than in rat brain [75]. These results suggested that less lipophilic and/or higher affinity mGluR1 ligands are necessary for successful imaging in the primate brain.


Development of PET and SPECT probes for glutamate receptors.

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

Chemical structure of imaging probes for mGluR1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig7: Chemical structure of imaging probes for mGluR1.
Mentions: (3-Ethyl-2-[11C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl)methanone ([11C]JNJ-16567083, Figure 7) has been developed as a high-affinity, selective mGluR1 ligand (Ki = 4.41 nM for rat mGluR1, 13.3 nM for human mGluR1) [74]. Ex vivo studies using this ligand showed good brain uptake and a localization pattern consistent with mGluR1 expression. In addition, over 80% of the accumulation of [11C]JNJ-16567083 in the cerebellum was blocked by selective mGluR1 antagonists, while treatment with a selective mGluR5 antagonist produced no marked inhibition of its binding, indicating selectivity for mGluR1. In PET studies, it showed high specific binding in regions expressing mGluR1, indicating that [11C]JNJ-16567083 is bound to mGluR1 in the living rat brain [74]. An 18F-labeled JNJ-16567083 derivative ([18F]12, Figure 7) was also reported to have a high affinity for mGluR1 (Ki = 1.77 nM for rat mGluR1 and 24.4 nM for human mGluR1). The in vivo localization of [18F]12 in rats was similar to that of [11C]JNJ-16567083. The in vivo accumulation of [18F]12 in the cerebellum was inhibited by pretreatment with a selective mGluR1 antagonist, but not by an mGluR2 antagonist (LY341495) or an mGluR5 antagonist (MPEP), indicating selectivity for mGluR1 in the living rat brain. However, PET studies in baboons found that [11C]JNJ-16567083 and [18F]12 produced low brain signals, probably due to a lower receptor density in baboon brain than in rat brain [75]. These results suggested that less lipophilic and/or higher affinity mGluR1 ligands are necessary for successful imaging in the primate brain.

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