A variety of metal ions that span the entirety of the periodic table have potential applications in nuclear medicine.¹ To use them in this context, it is usually necessary to stably ligate these metal ions with a chelator to provide control over their biodistribution and target them to diseased tissue.² Because of the great diversity in the chemical properties of the many radiometals of interest for nuclear medicine, a wide range of different chelators must be developed for using each distinct ion in this application. However, if a single chelator could be designed to bind all these metal ions with disparate properties equally well, their implementation in different radiopharmaceutical agents and nuclear medicine would be substantially facilitated, especially for situations where two or more metal ions are required for diagnosis and therapy. In this presentation, we describe our efforts to address this challenge by designing and exploring a class of 18-membered macrocyclic ligands, which show an unprecedented size-selectivity pattern that is exemplified by studies on their lanthanide (Ln³⁺) coordination chemistry.^3,4 We present a structure-activity relationship for how modifications of these ligands affect their thermodynamic and kinetic stabilities with the lanthanide ions, using a range of techniques like potentiometric and UV–Vis spectroscopic titrations, X-ray crystallography, NMR spectroscopy, and DFT calculations. Lastly, their abilities to bind to medicinally relevant radiometals are described. Collectively, this work highlights novel ligand design strategies for medically relevant Ln³⁺ ions. The demonstration that these ligands work effectively for both large and small Ln³⁺ ions leads us closer to developing a true “Jack of All Trades” chelator for nuclear medicine applications.

Dariusz Smilowicz

Appearances