Molecular Imaging of Alzheimer's Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic ¹⁸ F-deoxyfluorination Probe

Sigma-1 receptor (sigma R-1) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain sigma R-1 could provide a powerful tool for better understanding the underlying pathomechanism of sigma R-1 in AD. In this study, we successfully developed a F-18-labeled sigma R-1 radiotracer [F-18]CNY-05 via an innovative ruthenium (Ru)-mediated F-18-deoxyfluorination method. [F-18]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [F-18]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [F-18]CNY-05 in the AD mouse model found a significantly decreased brain uptake compared to that in wild-type mice. Collectively, we have provided a novel F-18-radiolabeled sigma R-1 PET probe, which enables visualizing brain sigma R-1 in health and neurological diseases.