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Pharmacokinetics, biodistribution and brain retention of a bispecific antibody-based PET radioligand for imaging of amyloid-beta
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 17254Article in journal (Refereed) Published
Abstract [en]

Monoclonal antibodies (mAbs) have not been used as positron emission tomography (PET) ligands for in vivo imaging of the brain because of their limited passage across the blood-brain barrier (BBB). However, due to their high affinity and specificity, mAbs may be an attractive option for brain PET if their brain distribution can be facilitated. In the present study, a F(ab')(2) fragment of the amyloidbeta (A beta) protofibril selective mAb158 was chemically conjugated to the transferrin receptor (TfR) antibody 8D3 to enable TfR mediated transcytosis across the BBB. The generated bispecific protein, 8D3-F(ab')(2)-h158, was subsequently radiolabeled and used for microPET imaging of A beta pathology in two mouse models of AD. [124I]8D3-F(ab')(2)-h158 was distributed across the BBB several fold more than unmodified mAbs in general and its accumulation in the brain reflected disease progression, while its concentration in blood and other organs remained stable across all age groups studied. Cerebellum was largely devoid of 8D3-F(ab')(2)-h158 in young and middle aged mice, while mice older than 18 months also showed some accumulation in cerebellum. In a longer perspective, the use of bispecific antibodies as PET ligands may enable in vivo 'immunohistochemistry' also of other proteins in the brain for which PET radioligands are lacking.

Place, publisher, year, edition, pages
2017. Vol. 7, article id 17254
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
URN: urn:nbn:se:uu:diva-343897DOI: 10.1038/s41598-017-17358-2ISI: 000417463500053PubMedID: 29222502OAI: oai:DiVA.org:uu-343897DiVA, id: diva2:1187222
Funder
Swedish Research Council, 2012-1593Available from: 2018-03-02 Created: 2018-03-02 Last updated: 2018-03-08Bibliographically approved

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Sehlin, DagFang, Xiaotian T.Meier, Silvio R.Syvänen, Stina

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