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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

Sagittal PET images (0–60 min) of [11C]ITMM in wild-type (a) and mGluR1 knockout (b) mice brains [83].
© Copyright Policy - open-access
Related In: Results  -  Collection


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fig8: Sagittal PET images (0–60 min) of [11C]ITMM in wild-type (a) and mGluR1 knockout (b) mice brains [83].

Mentions: N-Cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo [3,2-a]benzimidazole-2-carboxamide (YM-202074, Figure 7) has been reported as a high-affinity, selective mGluR1 ligand (Ki = 4.8 nM for rat mGluR1) with lower lipophilicity than JNJ-16567083 (logD = 2.7 versus 3.38). Although [11C]YM-202074 showed in vitro accumulation consistent with mGluR1 expression in the rat brain, PET studies in rats using this ligand demonstrated a low brain uptake and localization that was inconsistent with mGluR1-rich regions. These findings may be attributed to rapid ligand metabolism and the subsequent influx of radiometabolites into the brain [76]. 1-(2-Fluoro-3-pyridyl)-4-(2-propyl-1-oxoisoindoline-5-yl)-5-methyl-1H-1,2,3-triazole (MK-1312, Figure 7) has been developed as a potent mGluR1 ligand (IC50 = 4.3 nM for human mGluR1), with high selectivity and moderate lipophilicity (logP = 2.3). [18F]MK-1312 displayed similar in vitro localization to that of mGluR1 and highly selective binding. PET studies of this ligand in rhesus monkeys demonstrated rapid uptake kinetics, with no significant defluorination in brain. In addition, binding was inhibited by the mGluR1 antagonist, MK-5435, in a dose-dependent manner [77]. Although these results indicated that [18F]MK-1312 may be a promising PET ligand for mGluR1, no further clinical studies have been reported to date. 1-(2-Fluoro-3-pyridyl)-4-(2-isopropyl-1-oxoisoindoline-5-yl)-5-methyl-1H-1,2,3-triazole (FPIT, Figure 7), an MK-1312 derivative, has been reported as a selective mGluR1 ligand with an IC50 of 5.4 nM for human mGluR1 [77]. [18F]FPIT showed similar in vitro distribution to mGluR1 in both rat and monkey brains. In addition, its accumulation was selectively blocked by an mGluR1 ligand, indicating excellent specific binding (95%). PET/magnetic resonance imaging (MRI) studies of this ligand in rats and monkeys demonstrated a distribution that was consistent with that observed in vitro. Brain accumulation of [18F]FPIT was significantly inhibited by nonradioactive FPIT and by the mGluR1-selective ligand JNJ-16259865 [78]. Although [18F]FPIT has been demonstrated to be a prospective PET probe for mGluR1, further clinical studies have not yet been performed, probably due to the slow pharmacokinetics, and the influx of small levels of radiometabolites into the brain. 4-Fluoro-N-[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide (FITM, Figure 7) was developed as a potent mGluR1 antagonist (IC50 = 5.1 nM) with high selectivity [79] and low lipophilicity (logD = 1.46) [80]. In vitro and ex vivo binding of [18F]FITM matched the distribution of mGluR1, with high specific binding in mGluR1-rich regions [80]. [18F]FITM showed high brain uptake (>7% ID/g in mice) and metabolic stability, with 95% intact [18F]FITM detected in the rat brain 120 min after injection. Rat and monkey PET studies demonstrated a radioactive signal distribution consistent with that of the mGluR1, with very high specific binding. Kinetic analysis showed that the calculated VT values of [18F]FITM were also consistent with the localization of mGluR1 [81]. PET studies of [18F]FITM in rat brain that included blocking experiments determined Bmax⁡ and Kd values in several brain regions with moderate mGluR1 expression, such as the thalamus, hippocampus, striatum, and cingulate cortex, consistent with the density of mGluR1 in these regions. However, because of its relatively slow kinetics, Bmax⁡ and Kd values of [18F]FITM could not be measured in the mGluR1-rich cerebellum [82]. Although these findings have shown that [18F]FITM is a prospective PET radiotracer for mGluR1, no further clinical PET studies have been reported in the literature. It is reported that [18F]FITM could be prepared in poor radiochemical yields (14 ± 3%), probably due to using the 4-nitrobenzamide precursor [80]. It is suggested that optimized methods for radiosynthesis of [18F]FITM should be developed. N-[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-methoxy-N-methylbenzamide (ITMM, Figure 7) has been reported to be a highly potent and selective PET probe for mGluR1, with a Ki value of 12.6 nM (rat brain homogenate) and a logD value of 2.57. In vitro binding of [11C]ITMM was consistent with mGluR1 distribution, with high specific binding in mGluR1-rich regions. A PET study in rats found that [11C]ITMM displayed high brain uptake, with the highest uptake (in the cerebellum) being over 3.0 of the SUV (standardized uptake value). The in vivo distribution of [11C]ITMM was consistent with the in vitro data. The heterogeneous localization of [11C]ITMM was abolished by treatment with nonradioactive ITMM and an mGluR1-selective ligand. In addition, a PET study of [11C]ITMM in the mGluR1 knockout mouse demonstrated quite low uptake and homogeneous distribution of radioactivity in the brain (Figure 8) [83]. Furthermore, [11C]ITMM showed reduced accumulation in the ischemic brain and treatment with the neuroprotective agent, minocycline, which may inhibit mGluR1 activation, abolished this decrease of mGluR1 in the brain [84]. Because [11C]ITMM has been demonstrated to be a promising PET tracer for mGluR1, the first human PET studies have been performed. [11C]ITMM uptake increased gradually in the cerebellar cortex and VT in this brain region was 2.61, while VT was 0.53 in the mGluR1-poor pons. The rank order of [11C]ITMM uptake was consistent with mGluR1 expression levels in the human brain (Figure 9). Because [11C]ITMM showed relatively low uptake in the brain regions with a modest expression of mGluR1, such as the thalamus, hippocampus, and cerebral cortex, the [11C]ITMM signal in regions outside the cerebellum could be difficult to assess and this would make it hard to examine localization changes in these regions [85]. Nevertheless, [11C]ITMM could be used to evaluate alterations in cerebellar mGluR1 under pathological conditions. Further clinical studies may be needed to assess the usefulness of [11C]ITMM as a PET ligand for quantification of mGluR1.


Development of PET and SPECT probes for glutamate receptors.

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

Sagittal PET images (0–60 min) of [11C]ITMM in wild-type (a) and mGluR1 knockout (b) mice brains [83].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8: Sagittal PET images (0–60 min) of [11C]ITMM in wild-type (a) and mGluR1 knockout (b) mice brains [83].
Mentions: N-Cyclohexyl-6-{[N-(2-methoxyethyl)-N-methylamino]methyl}-N-methylthiazolo [3,2-a]benzimidazole-2-carboxamide (YM-202074, Figure 7) has been reported as a high-affinity, selective mGluR1 ligand (Ki = 4.8 nM for rat mGluR1) with lower lipophilicity than JNJ-16567083 (logD = 2.7 versus 3.38). Although [11C]YM-202074 showed in vitro accumulation consistent with mGluR1 expression in the rat brain, PET studies in rats using this ligand demonstrated a low brain uptake and localization that was inconsistent with mGluR1-rich regions. These findings may be attributed to rapid ligand metabolism and the subsequent influx of radiometabolites into the brain [76]. 1-(2-Fluoro-3-pyridyl)-4-(2-propyl-1-oxoisoindoline-5-yl)-5-methyl-1H-1,2,3-triazole (MK-1312, Figure 7) has been developed as a potent mGluR1 ligand (IC50 = 4.3 nM for human mGluR1), with high selectivity and moderate lipophilicity (logP = 2.3). [18F]MK-1312 displayed similar in vitro localization to that of mGluR1 and highly selective binding. PET studies of this ligand in rhesus monkeys demonstrated rapid uptake kinetics, with no significant defluorination in brain. In addition, binding was inhibited by the mGluR1 antagonist, MK-5435, in a dose-dependent manner [77]. Although these results indicated that [18F]MK-1312 may be a promising PET ligand for mGluR1, no further clinical studies have been reported to date. 1-(2-Fluoro-3-pyridyl)-4-(2-isopropyl-1-oxoisoindoline-5-yl)-5-methyl-1H-1,2,3-triazole (FPIT, Figure 7), an MK-1312 derivative, has been reported as a selective mGluR1 ligand with an IC50 of 5.4 nM for human mGluR1 [77]. [18F]FPIT showed similar in vitro distribution to mGluR1 in both rat and monkey brains. In addition, its accumulation was selectively blocked by an mGluR1 ligand, indicating excellent specific binding (95%). PET/magnetic resonance imaging (MRI) studies of this ligand in rats and monkeys demonstrated a distribution that was consistent with that observed in vitro. Brain accumulation of [18F]FPIT was significantly inhibited by nonradioactive FPIT and by the mGluR1-selective ligand JNJ-16259865 [78]. Although [18F]FPIT has been demonstrated to be a prospective PET probe for mGluR1, further clinical studies have not yet been performed, probably due to the slow pharmacokinetics, and the influx of small levels of radiometabolites into the brain. 4-Fluoro-N-[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide (FITM, Figure 7) was developed as a potent mGluR1 antagonist (IC50 = 5.1 nM) with high selectivity [79] and low lipophilicity (logD = 1.46) [80]. In vitro and ex vivo binding of [18F]FITM matched the distribution of mGluR1, with high specific binding in mGluR1-rich regions [80]. [18F]FITM showed high brain uptake (>7% ID/g in mice) and metabolic stability, with 95% intact [18F]FITM detected in the rat brain 120 min after injection. Rat and monkey PET studies demonstrated a radioactive signal distribution consistent with that of the mGluR1, with very high specific binding. Kinetic analysis showed that the calculated VT values of [18F]FITM were also consistent with the localization of mGluR1 [81]. PET studies of [18F]FITM in rat brain that included blocking experiments determined Bmax⁡ and Kd values in several brain regions with moderate mGluR1 expression, such as the thalamus, hippocampus, striatum, and cingulate cortex, consistent with the density of mGluR1 in these regions. However, because of its relatively slow kinetics, Bmax⁡ and Kd values of [18F]FITM could not be measured in the mGluR1-rich cerebellum [82]. Although these findings have shown that [18F]FITM is a prospective PET radiotracer for mGluR1, no further clinical PET studies have been reported in the literature. It is reported that [18F]FITM could be prepared in poor radiochemical yields (14 ± 3%), probably due to using the 4-nitrobenzamide precursor [80]. It is suggested that optimized methods for radiosynthesis of [18F]FITM should be developed. N-[4-[6-(Isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-methoxy-N-methylbenzamide (ITMM, Figure 7) has been reported to be a highly potent and selective PET probe for mGluR1, with a Ki value of 12.6 nM (rat brain homogenate) and a logD value of 2.57. In vitro binding of [11C]ITMM was consistent with mGluR1 distribution, with high specific binding in mGluR1-rich regions. A PET study in rats found that [11C]ITMM displayed high brain uptake, with the highest uptake (in the cerebellum) being over 3.0 of the SUV (standardized uptake value). The in vivo distribution of [11C]ITMM was consistent with the in vitro data. The heterogeneous localization of [11C]ITMM was abolished by treatment with nonradioactive ITMM and an mGluR1-selective ligand. In addition, a PET study of [11C]ITMM in the mGluR1 knockout mouse demonstrated quite low uptake and homogeneous distribution of radioactivity in the brain (Figure 8) [83]. Furthermore, [11C]ITMM showed reduced accumulation in the ischemic brain and treatment with the neuroprotective agent, minocycline, which may inhibit mGluR1 activation, abolished this decrease of mGluR1 in the brain [84]. Because [11C]ITMM has been demonstrated to be a promising PET tracer for mGluR1, the first human PET studies have been performed. [11C]ITMM uptake increased gradually in the cerebellar cortex and VT in this brain region was 2.61, while VT was 0.53 in the mGluR1-poor pons. The rank order of [11C]ITMM uptake was consistent with mGluR1 expression levels in the human brain (Figure 9). Because [11C]ITMM showed relatively low uptake in the brain regions with a modest expression of mGluR1, such as the thalamus, hippocampus, and cerebral cortex, the [11C]ITMM signal in regions outside the cerebellum could be difficult to assess and this would make it hard to examine localization changes in these regions [85]. Nevertheless, [11C]ITMM could be used to evaluate alterations in cerebellar mGluR1 under pathological conditions. Further clinical studies may be needed to assess the usefulness of [11C]ITMM as a PET ligand for quantification of mGluR1.

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