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 (ZAd), which prolongs the liquid state spin lattice relaxation time (T1) by up to 39 % in vitro. Measurements with ZA and ZAd 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 ZAd, potentially allowing for the characterization of rapid acidification/basification processes in vivo. Dynamic pH imaging: Deuteration significantly prolongs the spin lattice relaxation constant (T1) of hyperpolarized 13C zymonic acid, which is an accurate chemical‐shift‐based pH biosensor for in vitro and in vivo applications. The authors develop a robust and reliable method to observe pH changes caused by a simple chemical reaction with spatial and temporal resolution on a timescale of seconds.