title: Characterization of creatine guanidinium proton exchange by water-exchange (WEX) spectroscopy for absolute-pH CEST imaging in vitro.
abstract: Chemical exchange saturation transfer (CEST) enables indirect detection of small metabolites in tissue by MR imaging. To optimize and interpret creatine-CEST imaging we characterized the dependence of the exchange-rate constant k(sw) of creatine guanidinium protons in aqueous creatine solutions as a function of pH and temperature T in vitro. Model solutions in the low pH range (pH = 5-6.4) were measured by means of water-exchange (WEX)-filtered ¹H NMR spectroscopy on a 3 T whole-body MR tomograph. An extension of the Arrhenius equation with effective base-catalyzed Arrhenius parameters yielded a general expression for k(sw) (pH, T). The defining parameters were identified as the effective base-catalyzed rate constant k(b,eff) (298.15 K) = (3.009 ± 0.16) × 10⁹  Hz l/mol and the effective activation energy E(A,b,eff)  = (32.27 ± 7.43) kJ/mol at a buffer concentration of c(buffer)  = (1/15) M. As expected, a strong dependence of k(sw) on temperature was observed. The extrapolation of the exchange-rate constant to in vivo conditions (pH = 7.1, T = 37 °C) led to the value of the exchange-rate constant k(sw)  = 1499 Hz. With the explicit function k(sw) (pH, T) available, absolute-pH CEST imaging could be realized and experimentally verified in vitro. By means of our calibration method it is possible to adjust the guanidinium proton exchange-rate constant k(sw) to any desired value by preparing creatine model solutions with a specific pH and temperature.
authors.affiliation: Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Department of Medical Physics in Radiology, Heidelberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Goerke
authors.forename: Moritz
authors.initials: M
authors.lastname: Zaiss
authors.forename: Peter
authors.initials: P
authors.lastname: Bachert
mesh_terms: D003401:Creatine / Q000378:metabolism*; D019791:Guanidine / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D011522:Protons; D012996:Solutions; D013696:Temperature; D014867:Water / Q000378:metabolism*
chemical_list: D011522:Protons; D012996:Solutions; D014867:Water; D019791:Guanidine; D003401:Creatine
keywords: Arrhenius equation; CEST; WEX; chemical exchange; creatine; pH imaging