Abstract
Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. However, in the central nervous system, antibody uptake is limited by the blood–brain barrier (BBB). Here we present a PET ligand to be used for diagnosis and evaluation of treatment effects in Alzheimer's disease. The amyloid β (Aβ) antibody mAb158 is radiolabelled and conjugated to a transferrin receptor antibody to enable receptor-mediated transcytosis across the BBB. PET imaging of two different mouse models with Aβ pathology clearly visualize Aβ in the brain. The PET signal increases with age and correlates closely with brain Aβ levels. Thus, we demonstrate that antibody-based PET ligands can be successfully used for brain imaging.
Highlights
Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs
We show by PET imaging that the brain distribution of 124I-labelled fusion protein correlates closely with the age-dependent increase of amyloid b (Ab) pathology in the brains of two transgenic mouse models with Alzheimer’s disease (AD)-like pathology
All existing amyloid PET radioligands bind to the b-sheet structure of insoluble fibrillar Ab
Summary
Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands and are currently used to image various targets in peripheral organs. Among them is receptor-mediated transcytosis, where the antibody is fused to a molecule that binds to a blood–brain barrier (BBB) expressed receptor, for example, the transferrin or insulin receptor, which enables active transport across the BBB (Fig. 1a) This technique was pioneered by Pardridge and colleagues[31] in the 1990s, and has recently been implemented in AD therapy to decrease production[32,33] or increase degradation[34] of Ab. In the present study, a F(ab0)[2] fragment of h158 is chemically fused to a transferrin receptor (TfR) antibody[35] with the aim to create a PET ligand for specific imaging of soluble Ab protofibrils. We show by PET imaging that the brain distribution of 124I-labelled fusion protein correlates closely with the age-dependent increase of Ab pathology in the brains of two transgenic mouse models with AD-like pathology This new radioligand has the potential to become an important diagnostic tool in AD and the study demonstrates that bispecific radioligands based on antibodies can be applied in medical imaging of proteins associated with CNS disorders
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