Metabolic PCTA-BasedShift Reagents for the Detectionof 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 significantly 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 chemical exchange saturation transfer (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 the CEST spectra. <i>In vitro</i>, CEST MRI experiments proved that imaging extracellular lactate specifically with these complexes is feasible even in the presence of competing small metabolites in blood and in the tumor microenvironment. <i>In vivo</i> preclinical imaging showed that Yb-PCTA can be safely administered intravenously in mice to detect extracellular lactate noninvasively. This work contributes to the field of precision imaging in medicine and provides evidence that the PCTA-ligand is a valuable scaffold for developing molecular and metabolic imaging sensors.