Improved Visualization and Specific Binding for Metabotropic Glutamate Receptor Subtype 1 (mGluR1) Using [11C]ITMM with Ultra-High Specific Activity in Small-Animal PET

Yamasaki, Tomoteru; Fujinaga, Masayuki; Yui, Joji; Wakizaka, Hidekatsu; Ohya, Tomoyuki; Nengaki, Nobuki; Ogawa, Michio; Ikoma, Yoko; Hatori, Akiko; Xie, Lin; Kawamura, Kazunori; Zhang, Ming‐Rong

doi:10.1371/journal.pone.0130006

Cited by 8 publications

(6 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The two most superior in‐human tracers of mGluR1 are [ 18 F]FIMX and [ 11 C]ITMM (Yamasaki et al, 2015; Zanotti‐Fregonara et al, 2016). During both homologous and heterologous blocking analysis, both tracers showed a much lower signal and separation of brain heterogeneity.…”

Section: Methodsmentioning

confidence: 99%

“…The specificity of tracers is concluded by various preclinical experiments. [ 11 C]ITMM (Yamasaki et al, 2015) has significantly reduced uptake, whereas no reduction was observed in the uptake of other specific ligands. [ 18 F]FIMX (Zanotti‐Fregonara et al, 2016) was observed after the introduction of mGluR5, presenting the absence of specific affinity to this particular area.…”

Section: Methodsmentioning

confidence: 99%

“…[ 11 C]ITMM (Yamasaki et al, 2015) has significantly reduced uptake, whereas no reduction was observed in the uptake of other specific ligands. [ [ 11 C]ITMM showed many changes in ultra high molar rodent experiment, providing consideration that molar activity effectively influences the human subject study.…”

Section: Specificity and Pharmacokinetic Analysis Of Mglur1 Radioligandsmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

Singh

Srivastava

et al. 2023

Drug Development Research

View full text Add to dashboard Cite

The inadequate information about the in vivo pathological, physiological, and neurological impairments, as well as the absence of in vivo tools for assessing brain penetrance and the efficiency of newly designed drugs, has hampered the development of new techniques for the treatment for variety of new central nervous system (CNS) diseases. The searching sites such as Science Direct and PubMed were used to find out the numerous distinct tracers across 16 CNS targets including tau, synaptic vesicle glycoprotein, the adenosine 2A receptor, the phosphodiesterase enzyme PDE10A, and the purinoceptor, among others. Among the most encouraging are [ 18 F]FIMX for mGluR imaging, [ 11 C]Martinostat for Histone deacetylase, [ 18 F]MNI-444 for adenosine 2A imaging, [ 11 C]ER176 for translocator protein, and [ 18 F]MK-6240 for tau imaging. We also reviewed the findings for each tracer's features and potential for application in CNS pathophysiology and therapeutic evaluation investigations, including target specificity, binding efficacy, and pharmacokinetic factors. This review aims to present a current evaluation of modern positron emission tomography tracers for CNS targets, with a focus on recent advances for targets that have newly emerged for imaging in humans.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Specificity and Pharmacokinetic Analysis Of Mglur1 Radioligandsmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

Singh

Srivastava

et al. 2023

Drug Development Research

View full text Add to dashboard Cite

show abstract

“…An ultra-high molar activity study with 11 C-ITMM in rodents saw a significant increase in SUV and V T compared with standard molar activity, highlighting molar activity as a potential risk for introducing variability [238]. A study investigating the relationship of 11 C-ITMM V T with age and gender reported increases in V T in older controls [92].…”

Section: Pharmacokinetic Profile Of Mglur1 Tracersmentioning

confidence: 96%

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

102

View full text Add to dashboard Cite

Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

show abstract

“…N -[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-4-[ 11 C]methoxy- N -methyl-benzamide ([ 11 C]ITMM, 68 ), which was derived from the a potent negative allosteric modulator of mGluR1, has a K D of 13.6 nM in vitro [ 133 ]. Analysis of the uptake of high molar activity [ 11 C]ITMM ( 68 ) in rats with 90 min PET recordings gave V T ranging from 2 mL g −1 in pons to 8 mL g −1 in striatum and 15 mL g −1 in cerebellum, calculated relative to a metabolite-corrected input function [ 134 ]. In a preclinical stroke study, declining [ 11 C]ITMM ( 68 ) binding was indicative of the extent and progression of the ischemic brain injury [ 135 ].…”

Section: Glutamate Receptorsmentioning

confidence: 99%

A Review of Molecular Imaging of Glutamate Receptors

et al. 2020

View full text Add to dashboard Cite

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.

show abstract

Improved Visualization and Specific Binding for Metabotropic Glutamate Receptor Subtype 1 (mGluR1) Using [11C]ITMM with Ultra-High Specific Activity in Small-Animal PET

Cited by 8 publications

References 40 publications

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

Evaluation of advanced, pathophysiologic new targets for imaging of CNS

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

A Review of Molecular Imaging of Glutamate Receptors

Contact Info

Product

Resources

About