Targeted radionuclide therapy (TRT), including targeted alpha therapy (TAT), is a relatively new and highly promising approach to cancer therapy. It relies on bifunctional chelators (BFC) that, on the one hand, specifically target the cancer tissue via covalent attachment to a disease targeting vector, and on the other hand strongly encapsulate the radionuclide (227-Th, 225-Ac, 197-Hg, 89-Zr, etc.). An ideal BFC should be highly selective for the radionuclide of interest. As a further extension, the therapeutic function (by way of the radionuclide) is extended by diagnostic imaging to achieve theranostics that enables real-time monitoring of the radiopharmaceutical agents.

Computational quantum chemistry has reached a point where it can make meaningful contributions to ligand design for TRT, by providing (i) background information and understanding of the fundamental chemistry of radioactive elements, (ii) computational characterization of existing ligands and radionuclide metal complexes, (iii) proposing novel designs for TRT and theranostic agents. In our experience, this works particularly well if done in close collaborations with the broader experimental efforts.

In this presentation, I will present examples from our work in this area, illustrating some of the challenges, the computational approaches taken, and the questions to be asked.