SUMMARY
Treatment-resistant depression (TRD) affects 20-30% of major depressive disorder (MDD) patients and is
defined as a failure to respond to at least two adequate rounds of treatment with standard of care
antidepressants. TRD represents a substantial unmet medical need, requiring novel treatments with rapid and
sustained antidepressant activity and good safety and tolerability profiles. (S)-Ketamine (Spravato, Esketamine)
was recently approved for the treatment of TRD; however, it has several adverse side effects including sedation,
dissociative effects, and abuse liability. The precise mechanism of action (MOA) of ketamine remains unclear;
while described as a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, it has additional non-
NMDAR effects. In humans, ketamine is rapidly metabolized and some metabolites, such as (2R,6R)-
hydroxynorketamine (HNK), have rapid antidepressant-like activity in rodent models. The antidepressant-like
activity of HNK is partially mediated through metabotropic glutamate receptor subtype 2 (mGlu2). Thus, we
propose that negative allosteric modulation of mGlu2/3 represents a promising new strategy to treat TRD. Our
rationale is four-fold: (1) mGlu2/3 receptors are expressed in the forebrain regions affected in depression, with
particular enrichment in the medial prefrontal cortex, hippocampus and medial habenula, (2) inhibition of mGlu2/3
leads to molecular and cellular changes similar to those caused by ketamine, including α-amino-3-hydroxy-5-
methyl-4-isoxazolepropionic acid (AMPA) receptor potentiation, brain-derived neurotrophic factor (BDNF)
release, activation of mammalian target of rapamycin (mTOR) and ultimately synaptic remodeling, (3) mGlu2/3
orthosteric antagonists produce ketamine-like behavioral effects with sustained efficacy in multiple rodent
procedures that model aspects of depression, and (4) the antidepressant-like activity of the ketamine metabolite
(2R,6R)-HNK in rodent models is partially mediated by mGlu2. Thus, mGlu2/3 negative allosteric modulators
(NAMs) are predicted to produce antidepressant effects similar to ketamine without the psychotomimetic side
effects. Our objective is to advance a mGlu2/3 NAM into preclinical development and IND-enabling studies. To
this end, we have identified a lead and a backup mGlu2/3 NAM with excellent drug-like properties. The specific
aims are the following: (1) Determine the efficacy of our lead mGlu2/3 NAM in the rodent Probabilistic Reward
Task (PRT) and Effort-related Choice (ERC) task after acute oral dosing; and (2) Determine target engagement
of our lead mGlu2/3 NAM in vivo. On completion of this Phase I STTR, we will be able to determine if the lead
compound and/or the backup have the efficacy and pharmacological profile to be advanced into preclinical
development, which would become the basis of a Phase II application. Hence, the studies proposed here are
important precedents to support a future clinical program for MDD and TRD.
