Glutamate, the main excitatory neurotransmitter in the brain, acts on two distinct classes of receptors: the ionotropic (NMDA, AMPA, Kainate) and metabotropic glutamate (mGlu) receptors. The mGlu receptors play an important modulatory role in neurotransmission and are closely involved in a variety of physiological functions. Preclinical data support the therapeutic potential of negative allosteric modulation of the mGlu2 receptor in neuropsychiatric disorders such as depression and improvement in cognitive function in disorders like Alzheimer Disease. A high throughput screening (HTS) campaign resulted in an attractive pyrazole hit with moderate potency as negative allosteric modulator of the mGlu2 receptor. A focused medicinal chemistry optimization effort led to a lead compound with single digit nanomolar potency.1 Further evaluation of this lead, focused on reducing lipophilicity by means of a drastic change in the central scaffold, led to a pyrazolo-dihydropyrazinone bicycle with improved drug-like properties. Further optimization towards the ideal substitution pattern resulted in the selection of a candidate for clinical evaluation. In parallel to our Medicinal Chemistry efforts, we started a research program to discover an mGlu2 NAM-based PET radiotracer for in vivo imaging of this receptor in brain, applying our reported strategy.2 Several differently substituted derivatives framed within the pyrazolo-dihydropyrazinone bicycle were synthesized, containing motifs that could be eventually radiolabeled either with 11C or 18F. We will present the synthesis and biological evaluation of a set of compounds belonging to this new series of mGlu2 NAMs, and assessment as potential PET ligands of the most promising candidates.