Fluorine-18-Labeled Antibody Ligands for PET Imaging of Amyloid-β in Brain
| Autor: | Stina Syvänen, Johanna Rokka, Xiaotian T. Fang, Dag Erlend Olberg, Lars Lannfelt, Jonas Eriksson, Dag Sehlin, Rebecca Faresjö |
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| Rok vydání: | 2020 |
| Předmět: |
Genetically modified mouse
Fluorine Radioisotopes Physiology Cognitive Neuroscience Transferrin receptor Ligands trans-cyclooctene (TCO) Biochemistry Mice 03 medical and health sciences Tetrazine chemistry.chemical_compound 0302 clinical medicine inverse electron demand Diels−Alder reaction Animals Distribution (pharmacology) positron emission tomography (PET) 030304 developmental biology 0303 health sciences biology Chemistry Brain inverse electron demand Diels-Alder reaction Cell Biology General Medicine Receptor-mediated endocytosis Fluorine-18 In vitro Positron-Emission Tomography antibody radioligand biology.protein Biophysics tetrazine Radiologi och bildbehandling Antibody 030217 neurology & neurosurgery Research Article Radiology Nuclear Medicine and Medical Imaging Conjugate |
| Zdroj: | ACS Chemical Neuroscience |
| ISSN: | 1948-7193 |
| Popis: | Antibodies are attractive as radioligands due to their outstanding specificity and high affinity, but their inability to cross the blood–brain barrier (BBB) limits their use for CNS targets. To enhance brain distribution, amyloid-β (Aβ) antibodies were fused to a transferrin receptor (TfR) antibody fragment, enabling receptor mediated transport across the BBB. The aim of this study was to label these bispecific antibodies with fluorine-18 and use them for Aβ PET imaging. Bispecific antibody ligands RmAb158-scFv8D3 and Tribody A2, both targeting Aβ and TfR, were functionalized with trans-cyclooctene (TCO) groups and conjugated with 18F-labeled tetrazines through an inverse electron demand Diels–Alder reaction performed at ambient temperature. 18F-labeling did not affect antibody binding in vitro, and initial brain uptake was high. Conjugates with the first tetrazine variant ([18F]T1) displayed high uptake in bone, indicating extensive defluorination, a problem that was resolved with the second and third tetrazine variants ([18F]T2 and [18F]T3). Although the antibody ligands’ half-life in blood was too long to optimally match the physical half-life of fluorine-18 (t1/2 = 110 min), [18F]T3-Tribody A2 PET seemed to discriminate transgenic mice (tg-ArcSwe) with Aβ deposits from wild-type mice 12 h after injection. This study demonstrates that 18F-labeling of bispecific, brain penetrating antibodies is feasible and, with further optimization, could be used for CNS PET imaging. |
| Databáze: | OpenAIRE |
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