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Apr 1 – 5, 2019
Fairmont Château Laurier Hotel
UTC timezone

A Novel Reaction for “Click”-based 211At-Astatination

Not scheduled
Fairmont Château Laurier Hotel

Fairmont Château Laurier Hotel


Dr Christoph Denk (Vienna University of Technology)


**Purpose & Introduction** The α-emitter 211At is a highly promising radionuclide for targeted alpha therapy (TAT). High linear energy transfer renders alpha particles highly radio-toxic to adjacent cells, making TAT a efficient treatment option for cancer.[1] 211At is the only alpha emitter used in therapy that allows for covalent labeling, thus preventing the use of chelating ligands. In general, astatinations are carried out utilizing stannyl-precursors and oxidative conditions. Due to the low abundance of this element, the chemistry of astatine is rather unexplored. The availability of other straight forward radio-astatination procedures would extend the variety of accessible 211At-TAT agents, leading to more options in clinical research and the treatment of malignant disease. **Methods & Results** Within this contribution a novel methodology for introduction of 211At into small molecules is presented. In this multi-component labeling reaction, an azide-moiety (A), an alkyne-moiety (B), and 211At are combined using base and metal catalysis. The product formed consists of a 1,2,3-triazole (T) bearing both structural motifs (A and B) with the astatine located at the formed triazole system (A-T(211At)-B). The reaction, which has shown to be unaffected by high starting activities, was optimized towards reaction time and radiochemical yield (RCY), finally providing >70% RCY within 10 min. The reaction is highly tolerant considering the structural motifs A and B, as shown in a related study applying 125I as radioisotope.[2] This allows a high degree of structural variation, enabling straight-forward tuning of pharmacokinetic properties. We chose to use a biotin-azide as A and a tetrazine-alkyne as B, giving rise to a 211At agent that is suitable for biotin/streptavidin or tetrazine/trans-cyclooctene (TCO) based labeling and pre-targeting studies. The structure of the product was verified by binding experiments to TCO and streptavidin modified beads. Stability of the formed astatine-triazole bond was investigated by incubation of formed 211At-Beads in plasma for 300 min, showing 88% intact substance. Stability was further increased to 99% by click-assembly of a PEG-corona to the bead, using the tetrazine moiety of this multifunctional agent.   **Discussion & Conclusion** To the best of our knowledge we have developed a new, high yielding, fast and versatile labeling system for astatine-211. Applying this chemistry we were able to prepare the first 211At-labeled 1,2,4,5-tetrazine that furthermore bears a biotin functional motif. This agent is capable of binding to TCO and/or streptavidin in a highly efficient manner, thus providing a tool for pre-targeted alpha radiotherapy (pTAT) and macromolecule labeling. We are convinced that this new astatination-strategy is a step forward towards broader application of TAT by expanding the variety of 211At based therapeutic agents. [1]Elgqvist et al, Front Oncol. 2013. [2]Yan et al J. Am. Chem. Soc., 2013
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Presentation Type Contributed Oral

Primary author

Dr Christoph Denk (Vienna University of Technology)


Dr Emma Aneheim (University of Gothenburg, Sweden) Dr Martin Wilkovitsch (Vienna University of Technology) Dr Matthias Herth (Rigshospitalet, Copenhagen, DENMARK, University of Copenhagen, DENMARK) Dr Sture Lindegren (Departemnt of Radiation Physics, Institute of clinical Sciences Sahlgrenska Academy at Gotehnburg University)

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