薬物代謝と毒性学ジャーナル
オープンアクセス

概要

Metabolism Study of Fluor-Nitrophenylallylideneindolinone Ligand: A Radioimaging Agent for False Folded Alpha-Synuclein in the Diagnosis of Parkinson's Disease by High-Performance Liquid Chromatography and Tandem Mass Spectrometry

Weihsi Chen*, Kuanyin Chen, Tsungyu Shih, Siaosyun Guan, Shioushiow Farn

Background: The false folded protein of alpha (α) synuclein forms aggregation and causes neurodegenerative diseases known as α-synucleinopathies, such as Parkinson's disease. A radioactive fluor- labeled ligand, (Z)-{(fluoroethoxy) ethyl}-(E)-3-(4-nitrophenyl)-allylidene]-indolin-2-one (αsyn-18F), was synthesized and tested as a Positron Emission Tomography (PET) imaging agent for use in animal studies for the diagnosis of α-synucleinopathies.

Aim: To assess the synthetic products qualities of α-syn-F standard and its precursor, α-syn-Ms (Ms: methanesulfonate), determine the attendant impurities, and metabolites of α-syn-F in plasma, liver and brain biosystems.

Methods: Various sample solutions were analyzed via High-Performance Liquid Chromatography (HPLC) on a C18 column, with the identities determined via electrospray ionization-triple quardupole tandem mass spectrometry.

Results: The purities of α-syn-F and α-syn-Ms were both better than 94% with the major impurities being intermediate product residuals. The analytical method for tracing impurities in α-syn-F was applied to study the metabolites in various biomatrices, including rat liver microsomes, mice plasma, and liver and brain homogenate solutions. Here, seven, four, ten, and six metabolites were identified in the four biomatrices, respectively.

Conclusion: Biotransformation occurs in fluoroethoxyethyl, which results in the truncation and oxidation of the side chain and hydroxylation at the nitrophenylallylideneindolinone group before sulfonation, methylation, and glycine conjugation. A number of these metabolites lost their fluor and were not more traceable on the PET graph. The results suggest that PET imaging should be finalized within 30 min after intravenous administration of α-syn-F into the body.