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High detection sensitivity with antibody-based PET radioligand for amyloid beta in brain

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&NA; PET imaging of amyloid‐beta (A&bgr;) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new… Click to show full abstract

&NA; PET imaging of amyloid‐beta (A&bgr;) deposits in brain has become an important aid in Alzheimer's disease diagnosis, and an inclusion criterion for patient enrolment into clinical trials of new anti‐A&bgr; treatments. Available PET radioligands visualizing A&bgr; bind to insoluble fibrils, i.e. A&bgr; plaques. Levels of prefibrillar A&bgr; forms, e.g. soluble oligomers and protofibrils, correlate better than plaques with disease severity and these soluble species are the neurotoxic form of A&bgr; leading to neurodegeneration. The goal was to create an antibody‐based radioligand, recognizing not only fibrillary A&bgr;, but also smaller and still soluble aggregates. We designed and expressed a small recombinant bispecific antibody construct, di‐scFv 3D6‐8D3, targeting the A&bgr; N‐terminus and the transferrin receptor (TfR). Natively expressed at the blood‐brain barrier (BBB), TfR could thus be used as a brain‐blood shuttle. Di‐scFv 3D6‐8D3 bound to A&bgr;1‐40 with high affinity and to TfR with moderate affinity. Di‐scFv [124I]3D6‐8D3 was injected in two transgenic mouse models overexpressing human A&bgr; and wild‐type control mice and PET scanned at 14, 24 or 72 h after injection. Di‐scFv [124I]3D6‐8D3 was retained in brain of transgenic animals while it was cleared from wild‐type lacking A&bgr;. This difference was observed from 24 h onwards, and at 72 h, 18 months old transgenic animals, with high load of A&bgr; pathology, displayed SUVR of 2.2–3.5 in brain while wild‐type showed ratios close to unity. A subset of the mice were also scanned with [11C]PIB. Again wt mice displayed ratios of unity while transgenes showed slightly, non‐significantly, elevated SUVR of 1.2, indicating improved sensitivity with novel di‐scFv [124I]3D6‐8D3 compared with [11C]PIB. Brain concentrations of di‐scFv [124I]3D6‐8D3 correlated with soluble A&bgr; (p < 0.0001) but not with total A&bgr;, i.e. plaque load (p = 0.34). We have successfully created a small bispecific antibody‐based radioligand capable of crossing the BBB, subsequently binding to and visualizing intrabrain A&bgr; in vivo. The radioligand displayed better sensitivity compared with [11C]PIB, and brain concentrations correlated with soluble neurotoxic A&bgr; aggregates.

Keywords: radioligand; antibody based; 3d6 8d3; bgr; brain

Journal Title: NeuroImage
Year Published: 2019

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