Discovery of the Cyclic Form of MRI pH‐Sensor Z ‐OMPD Enables >5% 13 C Hyperpolarization by SABRE

Molecules capable of sensing pH have played a pivotal role in analytical and biomedical sciences for over a century. With the emergence of hyperpolarized MRI, rapid noninvasive and tomographic pH imaging within minutes has become a realistic and highly appealing option for clinical diagnosis and treatment. In this study, we uncover that the pH‐responsive behavior of the MRI‐based pH probe 2‐oxo‐4‐methyl‐3‐pentene‐1,5‐dioic acid (OMPD), particularly its pronounced pH‐dependent 13 C chemical shift changes, originates from a reversible cyclization process. We demonstrate that the cyclic lactol form of OMPD explains its favorable p K a (ca. 6.5) and its pronounced pH‐dependent NMR chemical shift changes. Guided by this mechanistic insight, we developed an optimized synthesis of the lactol and achieved over 50,000‐fold 13 C NMR signal enhancement (at 1 T) of OMPD using hyperpolarization via reversible exchange with parahydrogen. By elucidating the molecular basis of OMPD's sensing behavior and establishing an efficient parahydrogen‐based method for its hyperpolarization, this work represents a significant step toward broader preclinical and clinical implementation.