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Ketamine and Ceftriaxone-Induced Alterations in Glutamate Levels Do Not Impact the Specific Binding of Metabotropic Glutamate Receptor Subtype 5 Radioligand [F]PSS232 in the Rat Brain


Müller Herde, Adrienne; Boss, Silvan D; He, Yingfang; Schibli, Roger; Mu, Linjing; Ametamey, Simon M (2018). Ketamine and Ceftriaxone-Induced Alterations in Glutamate Levels Do Not Impact the Specific Binding of Metabotropic Glutamate Receptor Subtype 5 Radioligand [F]PSS232 in the Rat Brain. Pharmaceuticals, 11:83.

Abstract

Several studies showed that [C]ABP688 binding is altered following drug-induced perturbation of glutamate levels in brains of humans, non-human primates and rats. We evaluated whether the fluorinated derivative [F]PSS232 can be used to assess metabotropic glutamate receptor 5 (mGluR5) availability in rats after pharmacological challenge with ketamine, known to increase glutamate, or ceftriaxone, known to decrease glutamate. In vitro autoradiography was performed on rat brain slices with [F]PSS232 to prove direct competition of the drugs for mGluR5. One group of rats were challenged with a bolus injection of either vehicle, racemic ketamine, S-ketamine or ceftriaxone followed by positron emission tomography PET imaging with [F]PSS232. The other group received an infusion of the drugs during the PET scan. Distribution volume ratios (DVRs) were calculated using a reference tissue model. In vitro autoradiography showed no direct competition of the drugs with [F]PSS232 for the allosteric binding site of mGluR5. DVRs of [F]PSS232 binding in vivo did not change in any brain region neither after bolus injection nor after infusion. We conclude that [F]PSS232 has utility for measuring mGluR5 density or occupancy of the allosteric site in vivo, but it cannot be used to measure in vivo fluctuations of glutamate levels in the rat brain.

Abstract

Several studies showed that [C]ABP688 binding is altered following drug-induced perturbation of glutamate levels in brains of humans, non-human primates and rats. We evaluated whether the fluorinated derivative [F]PSS232 can be used to assess metabotropic glutamate receptor 5 (mGluR5) availability in rats after pharmacological challenge with ketamine, known to increase glutamate, or ceftriaxone, known to decrease glutamate. In vitro autoradiography was performed on rat brain slices with [F]PSS232 to prove direct competition of the drugs for mGluR5. One group of rats were challenged with a bolus injection of either vehicle, racemic ketamine, S-ketamine or ceftriaxone followed by positron emission tomography PET imaging with [F]PSS232. The other group received an infusion of the drugs during the PET scan. Distribution volume ratios (DVRs) were calculated using a reference tissue model. In vitro autoradiography showed no direct competition of the drugs with [F]PSS232 for the allosteric binding site of mGluR5. DVRs of [F]PSS232 binding in vivo did not change in any brain region neither after bolus injection nor after infusion. We conclude that [F]PSS232 has utility for measuring mGluR5 density or occupancy of the allosteric site in vivo, but it cannot be used to measure in vivo fluctuations of glutamate levels in the rat brain.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:29 August 2018
Deposited On:04 Dec 2018 15:03
Last Modified:04 Dec 2018 15:14
Publisher:MDPI Publishing
ISSN:1424-8247
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.3390/ph11030083
PubMed ID:30158438

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