Metabolic PCTA-Based Shift Reagents for the Selective Detection of Extracellular Lactate Using CEST MRI

Lactate is a key metabolic driver in oncology and immunology. Even in the presence of physiological oxygen levels, most cancer cells upregulate anaerobic glycolysis, resulting in abnormal lactate production and accumulation in the tumor microenvironment. The development of more effective, sensitive, and safe probes for detecting extracellular lactate holds the potential to impact cancer metabolic profiling and staging significantly. Macrocyclic-based PARACEST agents have been reported to act as shift reagents (SRs) and detect extracellular lactate via CEST MRI. Here, we introduce a new family of SRs based on the PCTA ligand, an inherently stable and kinetically inert group of molecules with the potential for (pre)clinical translation. We observed that Yb-PCTA and Eu-PCTA can significantly shift lactate -OH signals in CEST spectra. In vitro, CEST MRI experiments proved that imaging extracellular lactate with these complexes is feasible and maintains high specificity even in the presence of competing small metabolites in blood and the tumor microenvironment. In vivo, preclinical imaging demonstrated that Yb-PCTA can be safely administered intravenously in mice to detect extracellular lactate non-invasively. This work represents a significant step towards precision and molecular imaging, demonstrating that the PCTA-ligand is a promising scaffold for developing molecular imaging sensors. These chemical sensors have broad medical applications, particularly in oncology and physiology.