Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration

N-Methyl-d-aspartate receptors
are ionotropic
glutamate receptors that mediate fast excitatory neurotransmission
in the central nervous system. These receptors play essential roles
in synaptic plasticity, learning, and memory and are implicated in
various neuropathological and psychiatric disorders. Selective modulation
of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical
properties limit their in vivo utility. In this study, we optimized
the MPX-004/MPX-007 scaffold by modifying
the linker region between the distal halogenated aromatic ring and
the central pyrazine nucleus, resulting in the identification of potent
and selective compounds with improved drug-like properties. Notably,
compound 1 was used to develop the first GluN2A NAM-based
radioligand, and compound 11 showed improved pharmacokinetics
and dose-dependent receptor occupancy in vivo. Thus, we provide an
array of powerful new tools for the study of GluN2A receptors.