Development of a PET radioligand selective for cerebral amyloid angiopathy
| Autor: | Brian J. Lopresti, Guo-feng Huang, William E. Klunk, Chester A. Mathis, Jeffrey S. Stehouwer, Milos D. Ikonomovic, Eric E. Abrahamson, Alberto L. Vazquez, N. Scott Mason |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Amyloid Amyloid beta Article 030218 nuclear medicine & medical imaging Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine mental disorders medicine Radioligand Animals Radiology Nuclear Medicine and imaging Radioactive Tracers biology Chemistry Amyloidosis Brain Human brain medicine.disease Congo red Cerebral Amyloid Angiopathy medicine.anatomical_structure Positron-Emission Tomography 030220 oncology & carcinogenesis biology.protein Molecular Medicine Thioflavin Cerebral amyloid angiopathy |
| Zdroj: | Nucl Med Biol |
| ISSN: | 0969-8051 |
| DOI: | 10.1016/j.nucmedbio.2020.05.001 |
| Popis: | Introduction Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-β (Aβ) deposits in living people. However, this technique cannot distinguish between Aβ deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Aβ immunotherapies in AD patients, such as CAA. Methods A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Aβ fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. Results Compound 1 displays characteristics of Aβ binding dyes, such as thioflavin-S, in that it labels both parenchymal Aβ plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Aβ amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Aβ deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. Conclusion We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Aβ deposits in the vascular wall (i.e., “delivery selectivity”). |
| Databáze: | OpenAIRE |
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