Group II metabotropic glutamate (mGlu) receptor agonists were efficacious in randomized clinical research trials for schizophrenia and generalized anxiety disorder. The regional quantification of mGlu2 and mGlu3 receptors remains unknown. A selective and structurally novel mGlu2/3 receptor agonist, 2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY459477) was tritiated and the distribution of mGlu2 and mGlu3 receptors was studied in transgenic mice lacking either mGlu2, mGlu3 or both receptors. LY459477 is an agonist with 1–2 nM potency for rodent and human mGlu2 and mGlu3 receptors. The functional selectivity of LY459477 was demonstrated by over 640-fold selectivity and the displacement binding selectivity was greater than 320-fold for all glutamate receptors except mGlu6 (∼230-fold). More than 1000-fold selectivity was demonstrated for all non-glutamate receptors known to be targeted by antipsychotic drugs. Like atypical antipsychotic drugs, LY459477 reversed in vitro electrophysiological effects of a serotonergic hallucinogen and behavioral effects of phencyclidine or amphetamine. There was virtually no binding of [3H]LY459477 to any brain region in mice with a deletion of both mGlu2 and mGlu3 receptors. Regions enriched in mGlu2 receptors included the medial prefrontal cortex, select hippocampal regions, the medial mammillary nucleus, the medial habenula, and the cerebellar granular cell layer. Regions enriched in mGlu3 receptors were the dorsolateral entorhinal cortex, the hippocampal CA1 field, the piriform cortex, the substantia nigra, the thalamic reticular nucleus, and primary sensory thalamic nuclei. These findings suggest [3H]LY459477 should be a useful tool to further define the role of mGlu2 and mGlu3 receptors throughout the brain with respect to major neuropsychiatric syndromes.
This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.