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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

Ex vivo autoradiograms of [125I]CNS 1261 in the caudate nucleus (white arrow) and cerebral cortex (black arrow) of rat brain (a). Quantified regional isotope levels normalized to cerebellum (b). The animals were injected with [125I]CNS 1261 15 min after permanent occlusion of the middle cerebral artery (left hemisphere) and sacrificed 120 min later [26].
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fig2: Ex vivo autoradiograms of [125I]CNS 1261 in the caudate nucleus (white arrow) and cerebral cortex (black arrow) of rat brain (a). Quantified regional isotope levels normalized to cerebellum (b). The animals were injected with [125I]CNS 1261 15 min after permanent occlusion of the middle cerebral artery (left hemisphere) and sacrificed 120 min later [26].

Mentions: Open channel blockers of NMDARs, such as (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d] cyclohepten-5,10-diyldiammonium maleate (MK-801) and phencyclidine (PCP) derivatives, have been reported to bind to NMDARs in an activation-dependent manner [22, 23]. Thus, numerous in vivo imaging agents have been developed to interact with the PCP binding site, as this enables evaluation of the distribution of functional NMDARs in the brain under normal and pathological states. These agents include PCP, MK-801, ketamine, memantine, and diarylguanidine derivatives. [18F]1 (Figure 1), a PCP derivative with an IC50 of 61 nM for the ion channel site, showed an in vivo distribution that was consistent with NMDAR expression. Furthermore, coinjection of 1.7 μmol/kg of the high-affinity ion channel blocker, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane (cis-HPTC), resulted in a reduction in the regional cerebral distribution of [18F]1. However, this tracer was unsuitable for use as an NMDAR PET radioligand because of its high nonspecific binding in the brain [24]. A 3-[11C]cyano analog of MK-801 ([11C]MKC, Figure 1) has been reported as a PET ligand with excellent affinity for the channel blocker site (Kd = 8.2 nM). This tracer showed highly specific binding and heterogeneous in vitro distribution in rat brain slices that was similar to the expression of NMDARs. In PET studies, [11C]MKC showed a rapid and high uptake into the brains of rhesus monkeys, with higher accumulation in the frontal cortex than in the cerebellar cortex. However, these distribution patterns correlated closely with regional cerebral blood flow and blocking with NMDAR antagonists did not affect the regional brain distribution of this tracer [25]. PCP and MK-801 analogs showed high nonspecific in vivo binding, probably due to their high lipophilicity. Diarylguanidines have been identified as highly potent NMDAR channel blockers, with less hydrophobicity than PCP and MK-801. Therefore, several radiolabeled diarylguanidine analogs have been reported as PET or SPECT ligands. N-(1-naphthyl)-N′-(3-iodophenyl)-N′-methylguanidine (CNS 1261, Figure 1) has been developed as a high-affinity SPECT ligand for the ion channel site (Ki = 4.2 nM) with moderate lipophilicity (logD = 2.19). In ex vivo autoradiographic studies, [125I]CNS 1261 showed 2.4–2.9-fold higher uptake by the hippocampus than by the cerebellum in normal rat brains. This accumulation pattern was consistent with the pattern of NMDAR expression. In addition, investigation of [125I]CNS 1261 binding in a mouse model of cerebral ischemia revealed that [125I]CNS 1261 showed 2-fold higher uptake by the caudate nucleus in the ischemic hemisphere, as compared to the same region of the nonischemic hemisphere (Figure 2). This suggested that [125I]CNS 1261 bound selectively to activated NMDARs [26]. Based on this positive result, several clinical SPECT studies employing [123I]CNS 1261 have been performed. In healthy volunteers, no significant difference in the total distribution volume (VT) was observed between the NMDAR-rich regions (striatum, hippocampus, and frontal cortex) and the NMDAR-poor cerebellum [27, 28]. Numerous reports have suggested that hypofunction of NMDARs is associated with the pathophysiology of schizophrenia [29, 30]. It is reported that drug-free patients with schizophrenia showed reduced binding of [123I]CNS 1261 in the left hippocampus relative to the whole cortex, compared with healthy controls [31]. In contrast, a separate study demonstrated that VT values of [123I]CNS 1261 in drug-free or typical antipsychotic-treated schizophrenia patients did not differ significantly from those observed in the control group [32]. Therefore, these reports did not provide evidence to support the proposal that NMDARs could be imaged by SPECT using [123I]CNS 1261. N-(2-chloro-5-thiomethylphenyl)-N′-(3-[11C]methoxy-phenyl)-N′-methylguanidine [11C]GMOM (Figure 1) is a 11C-labeled diarylguanidine derivative with a high affinity for the ion channel site (Ki = 5.2 nM). In PET studies conducted in baboons, [11C]GMOM showed BBB permeability. However, brain distribution of [11C]GMOM was almost homogeneous and preadministration of MK801 did not significantly change the regional VT [33]. Another diarylguanidine derivative, N-(2-chloro-5-(methylmercapto)phenyl)-N′-[11C]methylguanidine monohydrochloride ([11C]CNS 5161, Figure 1), had excellent affinity for the ion channel site (Ki = 1.9 nM). [3H]CNS 5161 showed a heterogeneous in vivo distribution in rat brain and a cortex/cerebellum ratio of 1.4. Pretreatment with NMDA increased the hippocampus/cerebellum ratio to 1.6–1.9, while MK801 reduced the ratios to close to 1.0 [34]. Clinical PET studies using [11C]CNS 5161 indicated that the largest uptake occurred in the putamen and thalamus and the lowest uptake was observed in the cerebellum, but relatively low levels of radioactivity were detected in the NMDAR-rich hippocampus [35]. Further investigations are necessary in order to provide consistent evidence that these diarylguanidines can be used as PET or SPECT radioligands for the channel blocker binding site of the NMDAR. Recently, [18F]GE-179 (Figure 1), a high-affinity channel blocker (Ki = 2.4 nM) [36], was radiolabeled and used for PET imaging in healthy human subjects. Although this tracer showed high brain uptake, the VT of each region was correlated to cerebral blood flow rather than the levels of NMDAR expression. Further characterization of [18F]GE-179 may be necessary with in vivo PET studies using NMDAR-activated models [37].


Development of PET and SPECT probes for glutamate receptors.

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

Ex vivo autoradiograms of [125I]CNS 1261 in the caudate nucleus (white arrow) and cerebral cortex (black arrow) of rat brain (a). Quantified regional isotope levels normalized to cerebellum (b). The animals were injected with [125I]CNS 1261 15 min after permanent occlusion of the middle cerebral artery (left hemisphere) and sacrificed 120 min later [26].
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4385697&req=5

fig2: Ex vivo autoradiograms of [125I]CNS 1261 in the caudate nucleus (white arrow) and cerebral cortex (black arrow) of rat brain (a). Quantified regional isotope levels normalized to cerebellum (b). The animals were injected with [125I]CNS 1261 15 min after permanent occlusion of the middle cerebral artery (left hemisphere) and sacrificed 120 min later [26].
Mentions: Open channel blockers of NMDARs, such as (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d] cyclohepten-5,10-diyldiammonium maleate (MK-801) and phencyclidine (PCP) derivatives, have been reported to bind to NMDARs in an activation-dependent manner [22, 23]. Thus, numerous in vivo imaging agents have been developed to interact with the PCP binding site, as this enables evaluation of the distribution of functional NMDARs in the brain under normal and pathological states. These agents include PCP, MK-801, ketamine, memantine, and diarylguanidine derivatives. [18F]1 (Figure 1), a PCP derivative with an IC50 of 61 nM for the ion channel site, showed an in vivo distribution that was consistent with NMDAR expression. Furthermore, coinjection of 1.7 μmol/kg of the high-affinity ion channel blocker, cis-2-hydroxymethyl-r-1-(N-piperidyl)-1-(2-thienyl)cyclohexane (cis-HPTC), resulted in a reduction in the regional cerebral distribution of [18F]1. However, this tracer was unsuitable for use as an NMDAR PET radioligand because of its high nonspecific binding in the brain [24]. A 3-[11C]cyano analog of MK-801 ([11C]MKC, Figure 1) has been reported as a PET ligand with excellent affinity for the channel blocker site (Kd = 8.2 nM). This tracer showed highly specific binding and heterogeneous in vitro distribution in rat brain slices that was similar to the expression of NMDARs. In PET studies, [11C]MKC showed a rapid and high uptake into the brains of rhesus monkeys, with higher accumulation in the frontal cortex than in the cerebellar cortex. However, these distribution patterns correlated closely with regional cerebral blood flow and blocking with NMDAR antagonists did not affect the regional brain distribution of this tracer [25]. PCP and MK-801 analogs showed high nonspecific in vivo binding, probably due to their high lipophilicity. Diarylguanidines have been identified as highly potent NMDAR channel blockers, with less hydrophobicity than PCP and MK-801. Therefore, several radiolabeled diarylguanidine analogs have been reported as PET or SPECT ligands. N-(1-naphthyl)-N′-(3-iodophenyl)-N′-methylguanidine (CNS 1261, Figure 1) has been developed as a high-affinity SPECT ligand for the ion channel site (Ki = 4.2 nM) with moderate lipophilicity (logD = 2.19). In ex vivo autoradiographic studies, [125I]CNS 1261 showed 2.4–2.9-fold higher uptake by the hippocampus than by the cerebellum in normal rat brains. This accumulation pattern was consistent with the pattern of NMDAR expression. In addition, investigation of [125I]CNS 1261 binding in a mouse model of cerebral ischemia revealed that [125I]CNS 1261 showed 2-fold higher uptake by the caudate nucleus in the ischemic hemisphere, as compared to the same region of the nonischemic hemisphere (Figure 2). This suggested that [125I]CNS 1261 bound selectively to activated NMDARs [26]. Based on this positive result, several clinical SPECT studies employing [123I]CNS 1261 have been performed. In healthy volunteers, no significant difference in the total distribution volume (VT) was observed between the NMDAR-rich regions (striatum, hippocampus, and frontal cortex) and the NMDAR-poor cerebellum [27, 28]. Numerous reports have suggested that hypofunction of NMDARs is associated with the pathophysiology of schizophrenia [29, 30]. It is reported that drug-free patients with schizophrenia showed reduced binding of [123I]CNS 1261 in the left hippocampus relative to the whole cortex, compared with healthy controls [31]. In contrast, a separate study demonstrated that VT values of [123I]CNS 1261 in drug-free or typical antipsychotic-treated schizophrenia patients did not differ significantly from those observed in the control group [32]. Therefore, these reports did not provide evidence to support the proposal that NMDARs could be imaged by SPECT using [123I]CNS 1261. N-(2-chloro-5-thiomethylphenyl)-N′-(3-[11C]methoxy-phenyl)-N′-methylguanidine [11C]GMOM (Figure 1) is a 11C-labeled diarylguanidine derivative with a high affinity for the ion channel site (Ki = 5.2 nM). In PET studies conducted in baboons, [11C]GMOM showed BBB permeability. However, brain distribution of [11C]GMOM was almost homogeneous and preadministration of MK801 did not significantly change the regional VT [33]. Another diarylguanidine derivative, N-(2-chloro-5-(methylmercapto)phenyl)-N′-[11C]methylguanidine monohydrochloride ([11C]CNS 5161, Figure 1), had excellent affinity for the ion channel site (Ki = 1.9 nM). [3H]CNS 5161 showed a heterogeneous in vivo distribution in rat brain and a cortex/cerebellum ratio of 1.4. Pretreatment with NMDA increased the hippocampus/cerebellum ratio to 1.6–1.9, while MK801 reduced the ratios to close to 1.0 [34]. Clinical PET studies using [11C]CNS 5161 indicated that the largest uptake occurred in the putamen and thalamus and the lowest uptake was observed in the cerebellum, but relatively low levels of radioactivity were detected in the NMDAR-rich hippocampus [35]. Further investigations are necessary in order to provide consistent evidence that these diarylguanidines can be used as PET or SPECT radioligands for the channel blocker binding site of the NMDAR. Recently, [18F]GE-179 (Figure 1), a high-affinity channel blocker (Ki = 2.4 nM) [36], was radiolabeled and used for PET imaging in healthy human subjects. Although this tracer showed high brain uptake, the VT of each region was correlated to cerebral blood flow rather than the levels of NMDAR expression. Further characterization of [18F]GE-179 may be necessary with in vivo PET studies using NMDAR-activated models [37].

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