Synthesis and in vitro evaluation of fluorinated styryl benzazoles as amyloid-probes |
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Authors: | Ribeiro Morais Goreti Vicente Miranda Hugo Santos Isabel C Santos Isabel Outeiro Tiago F Paulo Antonio |
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Affiliation: | aUnidade de Ciências Químicas Radiofarmacêuticas, Instituto Tecnológico e Nuclear, Estrada Nacional 10, 2686 953 Sacavém, Portugal;bCell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649 028 Lisboa, Portugal;cInstituto de Fisiologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal;dDepartment of Neurodegeneration and Restaurative Research, University Medizin Göttingen, Waldweg 33, 37073 Göttingen, Germany |
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Abstract: | The formation of proteinaceous aggregates is a pathognomonic hallmark of several neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. To date, the final diagnostic for these diseases can only be achieved by immunostaining of post-mortem brain tissues with the commonly used congo red and Thioflavin T/S amyloid-dyes. The interest in developing amyloid-avid radioprobes to be used for protein aggregates imaging by positron emission tomography has grown substantialy, due to the promise in assisting diagnosis of these disorders. To this purpose, the present work describes the synthesis and characterization of four novel fluorinated styryl benzazole derivatives 1–4 by means of the Wittig reaction, as well as their in vitro evaluation as amyloid-probing agents. All compounds were obtained as mixtures of geometric E and Z isomers, with the preferable formation of the E isomer. Photoisomerization reactions allowed for the maximization of the minor Z isomers. The authentic 1–4E/Z isomers were isolated after purification by column chromatography under dark conditions. Profiting from the fluorescence properties of the different geometric isomers of 1–4, their binding affinities towards amyloid fibrils of insulin, α-synuclein and β-amyloid peptide were also measured. These compounds share similarities with Thioflavin T, interacting specifically with fibrillary species with a red-shift in the excitation wavelengths along with an increase in the fluorescence emission intensity. Apparent binding constants were determined and ranged between 1.22 and 23.96 μM−1. The present data suggest that the novel fluorinated styryl benzazole derivatives may prove useful for the design of 18F-labeled amyloid radioprobes. |
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Keywords: | Benzazoles Styryl derivatives Wittig reaction Fluorescence Amyloid fibrils Binding affinity |
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