Total Chemical Syntheses of the GM3 and F-GM3 Ganglioside Epitopes and Comparative Pre-Clinical Evaluation for Non-Invasive Imaging of Oligodendrocyte Differentiation.

Abstract

Gangliosides are intimately involved in a plenum of (neuro)inflammatory processes, yet progress in establishing structure-function interplay is frequently hindered by the availability of well-defined glycostructures. Motivated by the ubiquity of the ganglioside GM3 in chemical neurology, and in particular by its conspicuous presence in myelin, the GM3 epitope was examined with a view to preclinical validation as a tracer. The suitability of this scaffold for the noninvasive imaging of oligodendrocyte differentiation in Multiple sclerosis is disclosed. The stereocontrolled synthesis of a site-selectively fluorinated analogue (F-GM3) is also disclosed to enable a comparative analysis in oligodendrocyte (OL) differentiation. Whereas the native epitope caused a decrease in the viability in a dose-dependent manner, the addition of distinct F-GM3 concentrations over 48 h had no impact on the OL viability. This is likely a consequence of the enhanced hydrolytic stability imparted by the fluorination and highlights the potential of fluorinated glycostructures in the field of molecular imaging. Given the predominant expression of GM3 in oligodendrocytes and the capacity of GM3 to interact with myelin-associated proteins, this preclinical evaluation has revealed F-GM3 to be an intriguing candidate for neurological imaging.