Synthesis and biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents for NR2B subtype of NMDA receptor

Fuchigami, Takeshi; Yamaguchi, Hiroshi; Ogawa, Mikako; Le, Biao; Nakayama, Morio; Haratake, Mamoru; Magata, Yasuhiro

doi:10.1016/j.bmc.2010.08.053

Cited by 14 publications

(9 citation statements)

References 43 publications

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“…The benzamidazole 2-{[4-(4-iodobenzyl)piperidin-1-yl]methyl}benzimidazol-5-ol showed high affinity for the GluN2B subunit, with a K i of 7 nM against [ 3 H]ifenprodil binding to rat cortical synaptic membranes [ 83 ]. When labelled with iodine-125 it showed excellent properties for autoradiography in vitro, but only moderate cerebral uptake in rats (0.5% ID/g at 30 min post injection).…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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Molecular imaging with positron emission tomography (PET) and single photon emission computed tomography (SPECT) is a well-established and important in vivo technique to evaluate fundamental biological processes and unravel the role of neurotransmitter receptors in various neuropsychiatric disorders. Specific ligands are available for PET/SPECT studies of dopamine, serotonin, and opiate receptors, but corresponding development of radiotracers for receptors of glutamate, the main excitatory neurotransmitter in mammalian brain, has lagged behind. This state of affairs has persisted despite the central importance of glutamate neurotransmission in brain physiology and in disorders such as stroke, epilepsy, schizophrenia, and neurodegenerative diseases. Recent years have seen extensive efforts to develop useful ligands for molecular imaging of subtypes of the ionotropic (N-methyl-D-aspartate (NMDA), kainate, and AMPA/quisqualate receptors) and metabotropic glutamate receptors (types I, II, and III mGluRs). We now review the state of development of radioligands for glutamate receptor imaging, placing main emphasis on the suitability of available ligands for reliable in vivo applications. We give a brief account of the radiosynthetic approach for selected molecules. In general, with the exception of ligands for the GluN2B subunit of NMDA receptors, there has been little success in developing radiotracers for imaging ionotropic glutamate receptors; failure of ligands for the PCP/MK801 binding site in vivo doubtless relates their dependence on the open, unblocked state of the ion channel. Many AMPA and kainite receptor ligands with good binding properties in vitro have failed to give measurable specific binding in the living brain. This may reflect the challenge of developing brain-penetrating ligands for amino acid receptors, compounded by conformational differences in vivo. The situation is better with respect to mGluR imaging, particularly for the mGluR5 subtype. Several successful PET ligands serve for investigations of mGluRs in conditions such as schizophrenia, depression, substance abuse and aging. Considering the centrality and diversity of glutamatergic signaling in brain function, we have relatively few selective and sensitive tools for molecular imaging of ionotropic and metabotropic glutamate receptors. Further radiopharmaceutical research targeting specific subtypes and subunits of the glutamate receptors may yet open up new investigational vistas with broad applications in basic and clinical research.

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Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

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“…In order to assess the binding characteristics of 11 C-benzyl amidines, we performed in vitro binding studies using rat-brain cryosection according to our previous work. 9 A typical in vitro binding autoradiogram of [ 11 C]CBA, [ 11 C]NBA, and [ 11 C]QBA of rat-brain sagittal sections showed high-radioactivity signals in the forebrain regions (the cerebral cortex and hippocampus), known to be GluN2B-rich regions, and lower signals in the cerebellum, a GluN2B-poor region (Figure 2A-C, respectively). These distribution patterns were consistent with the mRNA distribution of the GluN2B subunit.…”

Section: In Vitro Studiesmentioning

confidence: 99%

“…7 Although these ligands showed an extremely high in vitro selectivity for the GluN2B subunit, none of them showed specific binding in vivo. [8][9][10][11] Claiborne et al reported N-(benzyl) amidine derivatives as orally efficacious GluN2B-selective NMDAR antagonists. 12 In addition, Curtis et al have reported that cinnamyl and 2-naphthyl analogs of benzyl amidine (CBA and NBA) have high-GluN2B selectivity, extremely high-binding affinity (the K i values of CBA, and NBA for [ 3 H] ifenprodil binding are 0.7 nM and 1.3 nM, respectively), and methoxy groups, which can be labeled with carbon-11.…”

Section: Introductionmentioning

confidence: 99%

“…Consequently, several studies have developed various radioligands for the GluN2B subunit of the NMDARs as shown in Figure A . Although these ligands showed an extremely high in vitro selectivity for the GluN2B subunit, none of them showed specific binding in vivo . Claiborne et al reported N ‐(benzyl) amidine derivatives as orally efficacious GluN2B‐selective NMDAR antagonists .…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and characterization of ¹¹C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors

Fuchigami

Fujimoto

Haradahira

et al. 2018

Labelled Comp Radiopharmac

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GluN2B‐containing NMDA receptors (NMDARs) play fundamental roles in learning and memory, although they are also associated with various brain disorders. In this study, we synthesized and evaluated three 11C‐labeled N‐benzyl amidine derivatives 2‐[11C]methoxybenzyl) cinnamamidine ([11C]CBA), N‐(2‐[11C]methoxybenzyl)‐2‐naphthamidine ([11C]NBA), and N‐(2‐[11C]methoxybenzyl)quinoline‐3‐carboxamidine ([11C]QBA) as PET radioligands for these receptors. The 11C‐benzyl amidines were synthesized via conventional methylation of corresponding des‐methyl precursors with [11C]CH3I. In vitro binding characteristics were examined in brain sagittal sections using various GluN2B modulators and off‐target ligands. Further, in vivo brain distribution studies were performed in normal mice. The 11C‐labeled benzyl amidines showed high‐specific binding to the GluN2B subunit at in vitro. In particular, the quinoline derivative [11C]QBA had the best binding properties in terms of high‐brain localization to GluN2B‐rich regions and specificity to the GluN2B subunit. Conversely, these 11C‐radioligands showed the brain distributions were inconsistent with GluN2B expression in biodistribution experiments. The majority of the radiolabeled compounds were identified as metabolized forms of which amido derivatives seemed to be the major species. Although these 11C‐ligands had high‐specific binding to the GluN2B subunit, significant improvement in metabolic stability is necessary for successful positron emission tomography (PET) imaging of the GluN2B subunit of NMDARs.

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“…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 [ 125 I] 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.…”

Section: Nmdarsmentioning

confidence: 99%

Development of PET and SPECT Probes for Glutamate Receptors

Fuchigami

Nakayama

Yoshida

2015

The Scientific World Journal

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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.

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Synthesis and biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents for NR2B subtype of NMDA receptor

Cited by 14 publications

References 43 publications

A Review of Molecular Imaging of Glutamate Receptors

A Review of Molecular Imaging of Glutamate Receptors

Synthesis and characterization of ¹¹C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors

Development of PET and SPECT Probes for Glutamate Receptors

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Synthesis and biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents for NR2B subtype of NMDA receptor

Cited by 14 publications

References 43 publications

A Review of Molecular Imaging of Glutamate Receptors

A Review of Molecular Imaging of Glutamate Receptors

Synthesis and characterization of 11C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors

Development of PET and SPECT Probes for Glutamate Receptors

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Synthesis and characterization of ¹¹C‐labeled benzyl amidine derivatives as PET radioligands for GluN2B subunit of the NMDA receptors