Molecular Imaging of Alzheimer’s Disease-Related Sigma-1 Receptor in the Brain <b><i>via</i></b> a Novel Ru-Mediated Aromatic ^<b>18</b>F-deoxyfluorination Probe

Abstract

Sigma-1 receptor (σ₁R) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σ₁R could provide a powerful tool for better understanding the underlying pathomechanism of σ₁R in AD. In this study, we successfully developed a ¹⁸F-labeled σ₁R radiotracer [¹⁸F]CNY-05 via an innovative ruthenium (Ru)-mediated ¹⁸F-deoxyfluorination method. [¹⁸F]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [¹⁸F]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [¹⁸F]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 ¹⁸F-radiolabeled σ₁R PET probe, which enables visualizing brain σ₁R in health and neurological diseases.