Esterase-Catalyzed Production of Hyperpolarized C-Enriched Carbon Dioxide in Tissues for Measuring PH

C Magnetic resonance imaging of hyperpolarized (HP) C-enriched bicarbonate (HCO) and carbon dioxide (CO) is a novel and sensitive technique for tissue pH mapping in vivo. Administration of the HP physiological buffer pair is attractive, but poor polarization and the short T of C-enriched inorganic bicarbonate salts are major drawbacks for this approach. Here, we report a new class of mixed anhydrides for esterase-catalyzed production of highly polarized CO and HCO in tissue. A series of precursors with different alkoxy and acyl groups were synthesized and tested for chemical stability and T. C-enriched ethyl acetyl carbonate (C-EAC) was found to be the most suitable candidate due to the relatively long T and good chemical stability. Our results showed that C-EAC can be efficiently and rapidly polarized using BDPA. HP C-EAC was rapidly hydrolyzed by esterase to C-enriched monoacetyl carbonate (C-MAC), which then decomposed to HP CO. Equilibrium between the newly produced CO and HCO was quickly established by carbonic anhydrase, producing a physiological buffer pair with C NMR signals that can be quantified for pH measurements. Finally, in vivo tissue pH measurements using HP C-EAC was successfully demonstrated in the liver of healthy rats. These results suggest that HP C-EAC is a novel imaging probe for in vivo pH measurements.