Developing radiopharmaceuticals using radiometals requires chelators that can generate stable and inert complexes. To produce stable complexes, one must identify a compatible match between the chelate and the metal coordination chemistry. Furthermore, chelators that can provide a suitable coordination environment for a range of radiometals are particularly useful for diagnostic and therapeutic (theranostic) applications.
Thiosemicarbazones and semicarbazones are versatile functional groups that can coordinate metal ions as neutral or anionic ligands with the resulting complexes displaying diverse coordination chemistry. This presentation will focus on our work developing bis(thiosemicarbazone) and bis(semicarbazone) chelators for radiometals relevant to nuclear medicine for imaging and treating cancer - 64Cu,[1]68Ga,[2]99mTc,[3]111In, 212/213Bi,[4] and 212Pb.[5]
The complexes were typically characterized by NMR spectroscopy, mass spectrometry, X-ray crystallography and DFT calculations. Formation kinetics and kinetic stability of the complexes were determined for acid dissociation, serum competition and transchelation. Radiolabelling efficiency was monitored as a function of chelator concentration, temperature and pH to determine maximum molar activity. Bifunctionalisation was demonstrated with the attachment of a prostate specific membrane antigen (PSMA) specific inhibitor. Cell studies were performed in PSMA-positive cell lines (PC3-PIP and LNCaP) and a PSMA-negative cell line (PC3). Small animal imaging and biodistribution studies were performed.
The efficient complexation and remarkable kinetic inertness of the radiolabelled complexes and the ability to bifunctionalise the chelators demonstrate the unique potential and versatility of thiosemicarbazones and semicarbazones for developing theranostic radiopharmaceuticals.