Stable Isotopically-Enriched D-Glucose: Strategies to Introduce Carbon, Hydrogen and Oxygen Isotopes at Various Sites

INTRODUCTION For many years stable isotopes were confined to the chemical laboratory, where they were used primarily to study reaction rates,1 reaction mechanisms,2 and molecular conformation.3,4 Recently, stable isotopically-enriched molecules have been playing increasing roles in biochemical studies, particularly as probes of in vitro biological metabolism5,6 and of biomacromolecular structure.7,8 These modern applications have been stimulated, in large part, by dramatic technical developments in nuclear magnetic resonance (NMR) spectroscopy9 and mass spectrometry (MS).10 Very-high field multinuclear high-resolution NMR in one-, two- and three- dimensions,11,12 and various volume-selective forms of NMR derived from topical magnetic resonance (TMR) spectroscopy,13 have become important analytical methods in the study of biological phenomena. TMR and related techniques such as ISIS (Image Selected In-Vivo Spectroscopy)14 and Spatially Resolved Spectroscopy (SPARS)15 are particularly attractive, as they permit high-resolution, volume-specific observations essential to non-invasive metabolic studies of intact organs and organisms. Magnetic resonance imaging (MRI)16 is now a standard clinical tool for non-invasive diagnosis of disease, especially cancer, in humans. Clinical MRI is confined currently to the observation of water protons in cells, but will likely become multinuclear (e.g., 7Li, 19F, 23Na, 31P, 13C) in the future.17