Synthesis and preliminary studies of C-labeled tetrahydro-1,7-naphthyridine-2-carboxamides for PET imaging of metabotropic glutamate receptor 2.

Selective modulation of metabotropic glutamate receptor 2 (mGlu) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu using positron emission tomography (PET) would allow for quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu. A focused small molecule library of mGlu NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu NAMs, among which compounds and were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the binding specificity and selectivity of [C] and [C] towards mGlu. binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [C] as most promising PET mGlu PET ligand. mGlu NAMs were synthesized in 14%-20% yields in five steps. NAMs and were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [C] and [C] displayed similar heterogeneous distribution by autoradiography, consistent with mGlu expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [C] demonstrated superior binding specificity compared to [C]. Further radiometabolite analysis of [C] showed excellent stability in the brain. Compound exhibited high affinity and excellent subtype selectivity, which was then evaluated by autoradiography and PET imaging study after labeling with carbon-11. Ligand [C], which we named [C]MG2-1904, demonstrated high brain uptake and excellent / specific binding towards mGlu with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.