Preclinical evaluation of [18F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

Golla, Sandeep S.V.; Klein, Pieter J.; Bakker, Jaco; Schuit, Robert C.; Christiaans, Johannes A. M.; Geest, Leo van; Kooijman, Esther; Oropeza-Seguias, Gisela M.; Langermans, Jan A. M.; Leysen, Josée E.; Boellaard, Ronald; Windhorst, Albert D.; Berckel, Bart N.M. van; Metaxas, Athanasios

doi:10.1016/j.nucmedbio.2014.09.006

Cited by 21 publications

(33 citation statements)

References 40 publications

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“…One of the studies was of patients aged 55 to 80 (40) and may be confounded by comorbid medical conditions, their treatment, and age-related brain changes. Nevertheless, a clear need exists to develop specific Glu receptor ligands for mGluRs and ionotropic Glu receptor subunits (45) to better understand abnormal glutamatergic neurotransmission and plasticity in depression.…”

Section: Dysregulation Of Glutamatergic and Gabaergic Neurotransmissimentioning

confidence: 99%

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Lener

Niciu

Ballard

et al. 2017

Biological Psychiatry

373

214

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In patients with major depressive disorder (MDD) or bipolar disorder (BD), abnormalities in excitatory and/or inhibitory neurotransmission and neuronal plasticity may lead to aberrant functional connectivity patterns within large brain networks. Network dysfunction in association with altered brain levels of glutamate (Glu) and gamma-aminobutyric acid (GABA) have been identified in both animal and human studies of depression. In addition, evidence of an antidepressant response to subanesthetic dose ketamine has led to a collection of studies that have examined neurochemical (e.g. glutamatergic and GABA-ergic) and functional imaging correlates associated with such an effect. Results from these studies suggest that an antidepressant response in association with ketamine occurs, in part, by reversing these neurochemical/physiological disturbances. Future studies in depression will require a combination of neuroimaging approaches from which more biologically homogeneous subgroups can be identified, particularly with respect to treatment response biomarkers of glutamatergic modulation.

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Section: Dysregulation Of Glutamatergic and Gabaergic Neurotransmissimentioning

confidence: 99%

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Lener

Niciu

Ballard

et al. 2017

Biological Psychiatry

373

214

View full text Add to dashboard Cite

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“…Some other compound classes are still under investigation, such as fluoroalkyl diarylaguanidine [22]. An [ 18 F] analog of CNS5161 was recently injected in humans and has yielded promising results [23], while [ 18 F]-PK209, a new derivative of fluoroalkyl diaryguanidine, has shown interesting results in terms of affinity and selectivity in monkeys [24]. The affinity of these compounds has not yet been tested specifically for extrasynaptic receptors.…”

Section: Introductionmentioning

confidence: 99%

Radiolabeling of [18F]-fluoroethylnormemantine and initial in vivo evaluation of this innovative PET tracer for imaging the PCP sites of NMDA receptors

Salabert

Fonta

Fontan

et al. 2015

Nuclear Medicine and Biology

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“…We report on the synthesis and in vitro binding properties of [ 3 H] GMOM. Similar to MK-801 48 and the diarylguanidine tracers, 15,39,43,49 GMOM is selective for the NMDA receptor ionophore.…”

Section: Discussionmentioning

confidence: 99%

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[³H]₃methoxy phenyl)‐N′‐methylguanidine ([³H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist

Metaxas

Berckel

Klein

et al. 2019

Pharmacology Res & Perspec

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Labeled with carbon‐11, N ‐(2‐chloro‐5‐thiomethylphenyl)‐ N ′‐(3‐methoxyphenyl)‐ N ′‐methylguanidine ([ 11 C]GMOM) is currently the only positron emission tomography (PET) tracer that has shown selectivity for the ion‐channel site of N ‐methyl‐D‐aspartate (NMDA) receptors in human imaging studies. The present study reports on the selectivity profile and in vitro binding properties of GMOM. The compound was screened on a panel of 80 targets, and labeled with tritium ([ 3 H]GMOM). The binding properties of [ 3 H]GMOM were compared to those of the reference ion‐channel ligand [ 3 H](+)‐dizocilpine maleate ([ 3 H]MK‐801), in a set of concentration‐response, homologous and heterologous inhibition, and association kinetics assays, performed with repeatedly washed rat forebrain preparations. GMOM was at least 70‐fold more selective for NMDA receptors compared to all other targets examined. In homologous inhibition and concentration‐response assays, the binding of [ 3 H]GMOM was regulated by NMDA receptor agonists, albeit in a less prominent manner compared to [ 3 H]MK‐801. Scatchard transformation of homologous inhibition data produced concave upward curves for [ 3 H]GMOM and [ 3 H]MK‐801. The radioligands showed bi‐exponential association kinetics in the presence of 100 μmol L −1 l ‐glutamate/30 μmol L −1 glycine. [ 3 H]GMOM (3 nmol L −1 and 10 nmol L −1 ) was inhibited with dual affinity by (+)‐MK‐801, ( R,S )‐ketamine and memantine, in both presence and absence of agonists. [ 3 H]MK‐801 (2 nmol L −1 ) was inhibited in a monophasic manner by GMOM under baseline and combined agonist conditions, with an IC 50 value of ~19 nmol L −1 . The non‐linear Scatchard plots, biphasic inhibition by open channel blockers, and bi‐exponential kinetics of [ 3 H]GMOM indicate a complex mechanism of interaction with the NMDA receptor ionophore. The implications for quantifying the PET signal of [ 11 C]GMOM are discussed.

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Preclinical evaluation of [18F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

Abstract: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [(18)F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.

Cited by 21 publications

References 40 publications

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Radiolabeling of [18F]-fluoroethylnormemantine and initial in vivo evaluation of this innovative PET tracer for imaging the PCP sites of NMDA receptors

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[³H]₃methoxy phenyl)‐N′‐methylguanidine ([³H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist

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Preclinical evaluation of [18F]PK-209, a new PET ligand for imaging the ion-channel site of NMDA receptors

Abstract: PK-209 targets the intrachannel site with high selectivity. Imaging of the NMDAr is feasible with [(18)F]PK-209, despite its fast metabolism. Further in vivo evaluation in humans is warranted.

Cited by 21 publications

References 40 publications

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Glutamate and Gamma-Aminobutyric Acid Systems in the Pathophysiology of Major Depression and Antidepressant Response to Ketamine

Radiolabeling of [18F]-fluoroethylnormemantine and initial in vivo evaluation of this innovative PET tracer for imaging the PCP sites of NMDA receptors

Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[3H]3methoxy phenyl)‐N′‐methylguanidine ([3H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist

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Binding characterization of N‐(2‐chloro‐5‐thiomethylphenyl)‐N′‐(3‐[³H]₃methoxy phenyl)‐N′‐methylguanidine ([³H]GMOM), a non‐competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist