A mass spectrometry-based method for the determination of in vivo biodistribution of tumor targeting small molecule-metal conjugates

Abstract

Nuclear medicine plays a key role in modern diagnosis and cancer therapy. The development of tumor targeting radionuclide conjugates (also named Small Molecule-Radio Conjugates - SMRCs) represents a significant improvement over the clinical use of metabolic radiotracers (e.g., [¹⁸F]-Fluorodeoxyglucose) for imaging and over the application of biocidal external beam radiations for therapy. During the discovery of SMRCs, molecular candidates must be carefully evaluated typically by performing biodistribution assays in preclinical tumor models. Quantification methodologies based on radioactive counts are typically demanding due to safety concerns, availability of radioactive material, and infrastructures. In this article, we report the development of a mass spectrometry (MS)-based method for the detection and quantification of small molecule-metal conjugates (SMMCs) as cold surrogates of SMRCs. We applied this methodology for the evaluation of the biodistribution of a particular class of tumor-targeting drug candidates based on ^natLu, ^natGa, ^natF and directed against Fibroblast Activation Protein (FAP). The reliability of the LC-MS analysis was validated by direct comparison of MSbased and radioactivity-based biodistribution data. Results show that MS biodistribution of stable isotope metal conjugates is an orthogonal tool for the preclinical characterization of different classes of radiopharmaceuticals.