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Group II metabotropic glutamate receptor agonist prodrugs LY2979165 and LY2140023 attenuate the functional imaging response to ketamine in healthy subjects

Abstract

Background

Aberrant glutamate neurotransmission, and in particular dysfunction of the N-methyl-d-aspartate receptor (NMDAR), has been implicated in psychiatric disorders and represents a novel therapeutic target. Low-dose administration of the NMDA antagonist ketamine in healthy volunteers elicits a strong blood oxygenation level dependent (BOLD) imaging signal that can be attenuated by pretreatment with single, therapeutically effective doses of marketed medicines interacting with the glutamate system.

Objective

To test the attenuation of the ketamine-induced BOLD signal by pretreatment with either a metabotropic glutamate receptor (mGluR) 2/3 or a mGluR2 agonist in healthy volunteers

Methods

We used a ketamine challenge pharmacological magnetic resonance imaging (phMRI) paradigm to assess the modulatory effects of single acute doses of LY2140023 (pomaglumetad methionil), the methionine prodrug of the mGluR2/3 agonist LY404039 (10, 40, and 160 mg; N = 16 subjects) and of LY2979165, and the alanine prodrug of the selective orthosteric mGluR2 agonist 2812223 (20 and 60 mg; N = 16 subjects).

Results

A reduction in the ketamine-evoked BOLD phMRI signal relative to placebo was observed at the highest doses tested of both LY2140023 and LY2979165. A relationship was observed between reduction of the BOLD signal and increasing plasma levels of 2812223 in the LY2979165 cohort.

Conclusions

These results identify pharmacologically active doses of the group II mGluR agonist prodrugs LY2140023 and LY2979165 in humans. They also extend the classes of compounds that have been experimentally shown to reverse the ketamine-evoked phMRI signal in humans, further supporting the use of this method as a neuroimaging biomarker for assessing functional effects.

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Acknowledgements

Authors SCRW and MAM acknowledge the ongoing support of the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The authors acknowledge Darren Wilbraham for overseeing the clinical assessments and monitoring for this study at the Quintiles Clinical Research Unit. The views expressed are those of the authors and not necessarily those of the NIHR, NHS, or the Department of Health.

Funding

The study was funded by Eli Lilly and Company.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mitul A. Mehta or Adam J. Schwarz.

Ethics declarations

This study was conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study protocol was approved by the ethics review board (ERB). Informed consent was obtained from all participants.

Conflict of interest

MAM has acted as a consultant for Taisho Pharmaceutical and Cambridge Cognition and has sat on the advisory board for FORUM Pharmaceuticals and Autifony (unpaid). He currently holds research grants from Johnson & Johnson. AJS, JM, KJ, and CB are all employees and stockholders of Eli Lilly and Company. ST-W was an Eli Lilly and Company employee when this study was carried out; she is currently employed by Astellas. BJK was an Eli Lilly and Company employee when this study was carried out; he is currently employed by Lundbeck LLC and a stockholder of Eli Lilly and Company. PDM is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. TP is an employee of the Psychosis Studies Dept., Institute of Psychiatry, King’s College, London, UK and receives funding in the form if a clinical research training fellowship from the Wellcome Trust (grant number 105758/Z/14/Z). TM is an employee of QuintilesIMS and is supported by the NIHR Biomedical Research Centre at Guy’s and St. Thomas’ Hospitals and King’s College London. SCRW has received project funding from Pfizer, Takeda, GSK, Eli Lilly and Company, Johnson & Johnson, Roche, Evotec, Bionomics, GE Healthcare, and P1Vital. He has also previously acted as a consultant for GE Healthcare, GSK, Novartis, and Takeda. VK and AS declare that they have no conflict of interest.

Additional information

Juliet McColm, Sitra Tauscher-Wisniewski, and Bruce J. Kinon were employed at Eli Lilly and Company when the study was conducted.

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Mehta, M.A., Schmechtig, A., Kotoula, V. et al. Group II metabotropic glutamate receptor agonist prodrugs LY2979165 and LY2140023 attenuate the functional imaging response to ketamine in healthy subjects. Psychopharmacology 235, 1875–1886 (2018). https://doi.org/10.1007/s00213-018-4877-9

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  • DOI: https://doi.org/10.1007/s00213-018-4877-9

Keywords

  • phMRI
  • fMRI
  • Ketamine
  • mGlu
  • Glutamate
  • Pharmacological