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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.

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We are grateful to the Martinos Center radiopharmacy staff (Judit Sore, Kari Phan, Garima Gautam, and Samantha To) for help with radiotracer production. We are grateful to Brendan Taillon for assisting with rodent PET-CT studies. This research was supported by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy under Grant DE-SC0008430 (C.W.). This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, Grant Number: S10RR015728.

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Correspondence to Changning Wang.

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Zhu, Y., Fiedler, S.A., Hibert, M.L. et al. Synthesis of a carbon-11 radiolabeled BACE1 inhibitor. Med Chem Res 29, 262–267 (2020).

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  • BACE1
  • PET
  • Imaging