Pharmacological characterization of 3H‐HYDIA a new tritiated ligand selective for mGlu2/3 receptors

Abstract

Metabotropic glutamate receptor 2 and 3 have been involved in dementia, depression and schizophrenia and selective ligands are under development. This study contains the pharmacological characterization of a new radioligand 3H‐HYDIA: the selective and competitive mGlu2/3 antagonist (1S,2R,3R,5R,6S)‐2‐amino‐3‐hydroxy‐3‐tritio‐bicyclo[3.1.0]hexane‐2,6‐dicarboxylic acid RO0653479‐002‐002. This radioligand was generated after the observation that the introduction of the R‐configurated 3‐hydroxy‐group was sufficient to turn the potent mGlu2/3 agonist LY354740 into a selective mGlu2/3 antagonist (see Woltering T. J. et al. ChemMedChem 2007). The in vitro binding of 3H‐HYDIA was characterized in recombinant rat and human mGlu2 and mGlu3, in rat cortical and hippocampal membranes as well as in rat brain sections. Ionotropic glutamate receptor ligands, group I and III selective mGlu receptor ligands and negative allosteric modulators for group II mGlus did not inhibit 3H‐HYDIA binding. Several known mGluII ligands e.g. LY341495, LY354740, MGS0039, (2S,2′R,3′R)‐2‐(2′,3′‐dicarboxycyclopropyl)glycine, glutamate, completely inhibited the specific binding. This radioligand, a unique molecule interacting at the ortosteric binding site of the receptors, may serve as useful tools for the study of the molecular determinants of activity in the glutamate binding pocket of mGlu2/3.