The design, synthesis and SAR studies of novel 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) are presented in this letter. Starting from a HTS hit compound (1, IC50=477nM), optimization of various groups led to the synthesis of a potent mGluR5 NAM (32, IC50=75nM) with excellent rat PK profile and good brain penetration. This compound produced oral antidepressant-like effect in a mouse tale suspension model (MED: 30mg/kg).