Synthesis of a carbon-11 radiolabeled BACE1 inhibitor

Beta-secretase (BACE1), a transmembrane aspartyl protease, can cleave membrane-bound β-amyloid precursor proteins (APPs) to initiate the accumulation of amyloid-β (Aβ). The inhibition of BACE-1 to limit the accumulation of neurotoxic Aβ peptides could offer a potential treatment for Alzheimer’s Disease (AD). However, little is known about the distribution and density of BACE1 in the central nervous system. As a step toward filling this gap in knowledge, we have evaluated a potential radiotracer for the imaging of BACE1 using positron emission tomography (PET). A BACE1 inhibitor, 5, is reported with blood-brain barrier (BBB) permeability and high binding affinity. To characterize the pharmacokinetics and distribution of 5 in the brain, we radiolabeled 5 with carbon-11. Using PET, we found that [11C]5 shows moderate uptake in the brain when administered intravenously to rodents and further work will be performed in animal models to test its application as a PET imaging probe for the central nervous system. Our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for BACE1 inhibitors, crucial for the development of treatments for AD where CNS penetration is critical.