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

Area of Science:

• Biomedical Imaging
• Molecular Imaging
• Metabolic Imaging

Background:

• Lactate is a key metabolic driver in cancer, often accumulating in the tumor microenvironment due to upregulated anaerobic glycolysis.
• Current methods for detecting extracellular lactate have limitations in sensitivity, specificity, and safety.
• Developing novel probes for lactate detection is crucial for advancing cancer metabolic profiling and staging.

Purpose of the Study:

• To introduce a new family of macrocyclic-based shift reagents (SRs) for detecting extracellular lactate using CEST MRI.
• To evaluate the efficacy and specificity of these novel SRs in complex biological environments.
• To assess the safety and noninvasive potential of these agents for in vivo imaging.

Main Methods:

• Synthesis and characterization of novel PCTA-ligand based shift reagents (Yb-PCTA and Eu-PCTA).
• In vitro CEST MRI experiments to assess lactate detection in the presence of competing metabolites.
• In vivo preclinical CEST MRI studies in mice to evaluate safety and efficacy of Yb-PCTA for noninvasive lactate detection.

Main Results:

• Yb-PCTA and Eu-PCTA effectively shifted lactate -OH signals in CEST spectra.
• In vitro studies confirmed specific imaging of extracellular lactate, even with interfering blood metabolites.
• In vivo studies demonstrated safe intravenous administration of Yb-PCTA and successful noninvasive detection of extracellular lactate.

Conclusions:

• PCTA-ligand based shift reagents are effective for detecting extracellular lactate via CEST MRI.
• These novel agents show potential for specific and noninvasive cancer metabolic imaging.
• The PCTA scaffold is a promising platform for developing advanced molecular and metabolic imaging sensors for precision medicine.