Sigma-1 receptor as a diagnostic and imaging biomarker: Advances in translational research

The sigma-1 receptor ( σ 1 R) is an evolutionarily conserved, ligand-responsive chaperone enriched at ER–mitochondria contact sites that coordinates Ca 2+ signaling, proteostasis, and stress adaptation. By shaping synaptic function, neuroinflammation, and mitochondrial resilience, σ 1 R acts as a convergent node across neurodegenerative diseases, psychiatric, and pain disorders. In parallel, σ 1 R -selective positron emission tomography (PET) radioligands now enable quantitative, noninvasive measurement of receptor availability, supporting patient stratification and target-engagement readouts for σ1R-directed therapeutics. This review summarizes core mechanisms of σ 1 R biology, surveys disease-associated alterations with emphasis on Alzheimer’s (AD), Parkinson’s disease (PD) and evaluates the current σ 1 R PET toolbox with key quantitative considerations. We outline practical probe-design principles, focusing on pharmacophore constraints, derivatization exit vectors, and linker/tag engineering that preserve binding geometry. These advances position the field for harmonized multicenter imaging studies and integrated chemical-biology tools linking σ 1 R occupancy to cellular and circuit phenotypes, thereby accelerating biomarker validation and mechanism-guided therapy development.