Abstract by Rocío García Vázquez

The use of nanomedicines in nuclear medicine has gained great popularity in recent years. This is because antibodies, proteins, nanoparticles or polymers have unique properties to target certain tissues with high affinity and selectivity. They can also be used as drug delivery vehicles. Consequently, nanomedicines can be used for diagnosis, disease monitoring and treatment. Unfortunately, nanomedicines possess slow pharmacokinetics. This leads to slow targeted accumulation and slow systemic elimination of these vectors. In order to use nanomedicines as radiopharmaceuticals, long-living radionuclides have to be used to be compatible with the aforementioned slow pharmacokinetics. This leads to unnecessary radiation burden to healthy tissues. A pioneering strategy to deal with this challenge is pretargeting. This novel method results in better contrast at earlier time points. It consists of two steps. First, a non- radiolabeled, tagged nanomedicine is administered and allowed to accumulate at the target site and be excreted for days. Next, a radiolabeled small molecule (effector molecule) is administered that will specifically and rapidly bind to the tag of the antibody. This process takes minutes rather than hours. As a result of this approach, higher target-to-background ratios and reduced radiation to healthy tissue is observed. Pretargeting allows, consequently, the use of short-lived radionuclides, such as 11C or 18F.

The most attractive strategy for pretargeting is based on the tetrazine ligation between trans-cyclooctenes (TCO) and tetrazines (Tz). This reaction exhibits fast reaction kinetics, selectivity and has already been successfully applied in vivo. Since 18F is the most commonly applied radionuclide for PET imaging, many efforts have been made to label Tzs with it. However, only poorly reactive Tzs could directly be labeled. Highly reactive Tzs appear to be too sensitive to bases. However, these properties are required for pretargeting. 11C-labeling has successfully been applied, but not many strategies are currently existing.

This Ph.D. thesis is addressing these challenges. I successfully developed methods to direct 18F-labeling highly reactive Tzs. These methods allowed to radiolabel a set of Tzs that were successfully applied in pretargeted experiments. Tumor-to-muscle ratios of 20 could be reached – 5-fold higher as state-of-the-art- tracers before this study. Moreover, Tzs have been developed that can enter into the brain and bind there to their targets. Pretargeting beyond the blood-brain-barrier was not possible beforehand. Moreover, I have established a new method to 11C-label Tzs.

In conclusion, I hope to have developed new methods and imaging agents that will bring pretargeting closer to clinical applications.