Development of Carbon‐11 Labeled Pyrimidine Derivatives as Novel Positron Emission Tomography (PET) Agents Enabling Brain Sigma‐1 Receptor Imaging

Abstract The sigma‐1 receptor (σ1R) is a stress‐activated chaperone protein that has emerged as a significant therapeutic target for neurodegenerative disorders. Developing effective positron emission tomography (PET) imaging probes targeting σ1R is crucial for visualizing its distribution and function in the brain, as well as facilitating related drug development. In this study, two novel 11 C‐labeled PET probes based on the structure of a potent σ1R ligand Lan‐0101 are designed and synthesized. PET imaging studies in mice reveal that [ 11 C]CNY‐01 exhibits good brain uptake and binding specificity. Subsequent evaluation in non‐human primates further demonstrates that [ 11 C]CNY‐01 displays favorable brain penetration, slow clearance kinetics, and characteristics of irreversible binding to its target in blockage experiments. To assess the clinical potential of the probe, both in vitro experiments and in vivo PET imaging using [ 11 C]CNY‐01 are conducted in Alzheimer's disease (AD) transgenic mouse models. These studies reveal a significant decrease in σ1R expression in the brain under conditions of AD amyloid pathology and microglial activation, highlighting the probe's sensitivity to disease‐related receptor changes. This work establishes [ 11 C]CNY‐01 as a promising tool for investigating the relationship between σ1R and neurological disorders, potentially advancing the understanding of σ1R's role in disease pathophysiology and therapeutic interventions.