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Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain

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journal contribution
posted on 22.01.2018 by Lei Zhang, Laigao Chen, Jason K. Dutra, Elizabeth M. Beck, Sangram Nag, Akihiro Takano, Nahid Amini, Ryosuke Arakawa, Michael A. Brodney, Leanne M. Buzon, Shawn D. Doran, Lorraine F. Lanyon, Timothy J. McCarthy, Kelly R. Bales, Charles E. Nolan, Brian T. O’Neill, Klaas Schildknegt, Christer Halldin, Anabella Villalobos
Alzheimer’s disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in the brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling. Further evaluation in an LC-MS/MS “cold tracer” study in rodents revealed high specific binding to BACE1 in brain. Upon radiolabeling, [18F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans.