The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils
Development of an α-synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-bin...
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SAGE Publishing
2018-09-01
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| Series: | Molecular Imaging |
| Online Access: | https://doi.org/10.1177/1536012118796297 |
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| author | Lee Josephson PhD Nancy Stratman MS YuTing Liu MS Fang Qian MS Steven H. Liang PhD Neil Vasdev PhD Shil Patel PhD |
| author_facet | Lee Josephson PhD Nancy Stratman MS YuTing Liu MS Fang Qian MS Steven H. Liang PhD Neil Vasdev PhD Shil Patel PhD |
| author_sort | Lee Josephson PhD |
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| description | Development of an α-synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-binding compounds. [ 3 H]BF-227 bound to α-Syn and amyloid β peptide (Aβ) fibrils with affinities (K D ) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as K i ) for α-Syn and Aβ fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the K i (Aβ)/K i (α-Syn) ratio, was 0.23 for BF-227. A similar or lower ratio was measured for analogues decorated with alkyl or oxyethylene chains attached to the oxygen at the 6 position of BF-227, suggesting a lack of involvement of the side chain in fibril binding. BF-227-like iodobenzoxazoles had lower affinities and poor α-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved α-Syn selectively having K i (Aβ)/K i (α-Syn) ranging from 2.2 to 5.1 with appreciable fibril affinity, although not sufficient to warrant further investigation. Compounds based on fluorobenzoxazoles might offer an approach to obtaining an α-Syn imaging agent with an appropriate affinity and selectivity. |
| format | Article |
| id | doaj-art-fcc99597a79242698251f810a781528a |
| institution | Kabale University |
| issn | 1536-0121 |
| language | English |
| publishDate | 2018-09-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Molecular Imaging |
| spelling | doaj-art-fcc99597a79242698251f810a781528a2025-02-03T10:13:00ZengSAGE PublishingMolecular Imaging1536-01212018-09-011710.1177/1536012118796297The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide FibrilsLee Josephson PhD0Nancy Stratman MS1YuTing Liu MS2Fang Qian MS3Steven H. Liang PhD4Neil Vasdev PhD5Shil Patel PhD6 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Biomarkers Preclinical Imaging and Pharmacology, Research and Early Development, Biogen, MA, USA Biologics Drug Discovery, Biogen, Cambridge, MA, USA Biologics Drug Discovery, Biogen, Cambridge, MA, USA Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Translational Imaging Engine, Eisai AiM Institute, MA, USA. Vasdev is now with Azrieli Centre for Neuro-Radiochemistry, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, CanadaDevelopment of an α-synuclein (α-Syn) positron emission tomography agent for the diagnosis and evaluation of Parkinson disease therapy is a key goal of neurodegenerative disease research. BF-227 has been described as an α-Syn binder and hence was employed as a lead to generate a library of α-Syn-binding compounds. [ 3 H]BF-227 bound to α-Syn and amyloid β peptide (Aβ) fibrils with affinities (K D ) of 46.0 nM and 15.7 nM, respectively. Affinities of BF-227-like compounds (expressed as K i ) for α-Syn and Aβ fibrils were determined, along with 5 reference compounds (flutafuranol, flutemetamol, florbetapir, BF-227, and PiB). Selectivity for α-Syn binding, defined as the K i (Aβ)/K i (α-Syn) ratio, was 0.23 for BF-227. A similar or lower ratio was measured for analogues decorated with alkyl or oxyethylene chains attached to the oxygen at the 6 position of BF-227, suggesting a lack of involvement of the side chain in fibril binding. BF-227-like iodobenzoxazoles had lower affinities and poor α-Syn selectivity. However, BF-227-like fluorobenzoxazoles had improved α-Syn selectively having K i (Aβ)/K i (α-Syn) ranging from 2.2 to 5.1 with appreciable fibril affinity, although not sufficient to warrant further investigation. Compounds based on fluorobenzoxazoles might offer an approach to obtaining an α-Syn imaging agent with an appropriate affinity and selectivity.https://doi.org/10.1177/1536012118796297 |
| spellingShingle | Lee Josephson PhD Nancy Stratman MS YuTing Liu MS Fang Qian MS Steven H. Liang PhD Neil Vasdev PhD Shil Patel PhD The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils Molecular Imaging |
| title | The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils |
| title_full | The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils |
| title_fullStr | The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils |
| title_full_unstemmed | The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils |
| title_short | The Binding of BF-227-Like Benzoxazoles to Human α-Synuclein and Amyloid β Peptide Fibrils |
| title_sort | binding of bf 227 like benzoxazoles to human α synuclein and amyloid β peptide fibrils |
| url | https://doi.org/10.1177/1536012118796297 |
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