Synthesis of N-Acetyl-D- and -L-Leucine-13C6 Tool Compounds in Neurodegenerative Disease.
Crepin D., McGown A., Shepherd D., Braine R., Sharma M., Nafie J., Ribeiro JG., Pantoş GD., Churchill G., Platt FM., Spencer J.
N-acetyl-L-leucine (levacetylleucine, ALL) is the neuroprotective enantiomer of the racemic antivertigo drug, Tanganil (acetyl-DL-leucine, ADLL). ALL has recently been clinically repurposed for the treatment of Niemann Pick disease type C1, a disorder characterised by lysosomal accumulation of glycolipids and cholesterol. Isotopically labelled ALL was required, as well as its negative control, D-enantiomer (ADL), to monitor the in vivo metabolic fate of the drug and to distinguish it from endogenous leucine and associated metabolites. Here, we describe the synthesis of N-acetyl-D- and -L-leucine-13C6, as well as N-acetyl-L-leucine-13C1, by N-acetylation of their amino acid precursors, their spectroscopic characterisation and stereochemical and stability studies. These investigations found that formation of the products, as well as their water-soluble sodium salt formulation, occurs without compromising stereochemical integrity.