Esterase-Catalyzed Production of Hyperpolarized 13 C-Enriched Carbon Dioxide in Tissues for Measuring pH

ACS Sens. 2018 Nov 26;3(11):2232-2236. doi: 10.1021/acssensors.8b01097. Epub 2018 Nov 9.

Abstract

13C Magnetic resonance imaging of hyperpolarized (HP) 13C-enriched bicarbonate (H13CO3-) and carbon dioxide (13CO2) 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 T1 of 13C-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 13CO2 and H13CO3- in tissue. A series of precursors with different alkoxy and acyl groups were synthesized and tested for chemical stability and T1. 13C-enriched ethyl acetyl carbonate (13C-EAC) was found to be the most suitable candidate due to the relatively long T1 and good chemical stability. Our results showed that 13C-EAC can be efficiently and rapidly polarized using BDPA. HP 13C-EAC was rapidly hydrolyzed by esterase to 13C-enriched monoacetyl carbonate (13C-MAC), which then decomposed to HP 13CO2. Equilibrium between the newly produced 13CO2 and H13CO3- was quickly established by carbonic anhydrase, producing a physiological buffer pair with 13C NMR signals that can be quantified for pH measurements. Finally, in vivo tissue pH measurements using HP 13C-EAC was successfully demonstrated in the liver of healthy rats. These results suggest that HP 13C-EAC is a novel imaging probe for in vivo pH measurements.

Keywords: 13C MRI; bicarbonate; carbon dioxide; esterase; ethyl acetyl carbonate; hyperpolarization; pH sensor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anhydrides / chemical synthesis
  • Anhydrides / chemistry
  • Anhydrides / metabolism
  • Animals
  • Bicarbonates / chemistry
  • Bicarbonates / metabolism
  • Carbon Dioxide / chemistry
  • Carbon Dioxide / metabolism*
  • Carbon Isotopes / chemistry
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Carbonic Anhydrases / metabolism
  • Esterases / metabolism*
  • Hydrogen-Ion Concentration
  • Liver / metabolism
  • Male
  • Rats, Sprague-Dawley
  • Swine

Substances

  • Anhydrides
  • Bicarbonates
  • Carbon Isotopes
  • Carbon Dioxide
  • Esterases
  • Carbonic Anhydrases
  • Carbon-13