Cross-Isotopic Bioorthogonal Tools as Molecular Twins for Radiotheranostic Applications.

Radiotheranostics are designed by labeling targeting (bio)molecules with radionuclides for diagnostic or therapeutic application. As the pharmacokinetics of therapeutic compounds play a pivotal rule, chemically closely related imaging agents are used to evaluate the overall feasibility of the therapeutic approach. 'Theranostic relatives' utilizing different elements are frequently used in clinical practice. However, variations in pharmacokinetics, biodistribution, and target affinity due to the different chemical properties of the radioisotopes remain as hurdles to the design of optimized clinical tools. Herein, we report on the design and synthesis of structurally identical compounds either for diagnostic (18F and a stable metal isotope) or therapeutic application (radiometal and stable 19F). Such 'molecular twins' have been prepared applying a modular strategy based on click chemistry that enables efficient radiolabeling of compounds containing a metal-complex and a tetrazine moiety. This additional bioorthogonal functionality can be used for subsequent radiolabeling of (bio)molecules or pretargeting approaches, which is demonstrated in vitro.