Discovery of the Cyclic Form of MRI pH-Sensor Z-OMPD Enables >5% ¹³C 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 ¹³C chemical shift changes, originates from a reversible cyclization process. We demonstrate that the cyclic lactol form of OMPD explains its favorable pK_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 ¹³C 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.