Deuteration of Hyperpolarized ¹³C-Labeled Zymonic Acid Enables Sensitivity-Enhanced Dynamic MRI of pH

Aberrant pH is characteristic of many pathologies such as ischemia, inflammation or cancer. Therefore, a non-invasive and spatially resolved pH determination is valuable for disease diagnosis, characterization of response to treatment and the design of pH-sensitive drug-delivery systems. We recently introduced hyperpolarized [1,5-¹³C₂]zymonic acid (ZA) as a novel MRI probe of extracellular pH utilizing dissolution dynamic polarization (DNP) for a more than 10000-fold signal enhancement of the MRI signal. Here we present a strategy to enhance the sensitivity of this approach by deuteration of ZA yielding [1,5-¹³C₂, 3,6,6,6-D₄]zymonic acid (ZA_d), which prolongs the liquid state spin lattice relaxation time (T₁) by up to 39 % in vitro. Measurements with ZA and ZA_d on subcutaneous MAT B III adenocarcinoma in rats show that deuteration increases the signal-to-noise ratio (SNR) by up to 46 % in vivo. Furthermore, we demonstrate a proof of concept for real-time imaging of dynamic pH changes in vitro using ZA_d, potentially allowing for the characterization of rapid acidification/basification processes in vivo.