A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases

The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate -the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure-activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).

Automated summary

The excitatory amino acid transporter 2 (EAAT2) is crucial for the clearance and recycling of glutamate, the major excitatory neurotransmitter in the brain. Dysfunctions in EAAT2 can lead to neurodegenerative diseases, such as ALS and AD. Detecting EAAT2 in the living human brain is important for improving diagnosis and therapy for these diseases. This article discusses the role of EAAT2 and presents potential activators for therapy and molecular imaging tools for diagnosis.