Abstract by Nadia Renée Bom Pedersen

Radiometal‑based theranostics have significantly shaped and advanced the clinical landscape of radiopharmaceuticals. In particular, the approvals of lutetium-177 (¹⁷⁷Lu)‑Lutathera and ¹⁷⁷Lu‑Pluvicto, and their demonstrated patient benefit in targeted radioligand therapy, represent major breakthroughs for the field. Among diagnostic radionuclides, radiohalogen fluorine-18 (¹⁸F) remains the gold standard, offering ideal decay characteristics and supported by an extensive production and distribution network. This creates a clear and urgent unmet need for a therapeutic radiohalogen counterpart capable of forming a theranostic pair with ¹⁸F.

This PhD thesis addresses that need by exploring the chemistry and translational challenges associated with the α‑emitting radiohalogen astatine-211 (²¹¹At), one of the most promising therapeutic nuclides in the emerging α‑(r)evolution. The work highlights ²¹¹At’s favorable decay properties, the rapidly expanding international network of handling and production facilities, and ongoing progress from preclinical investigations toward early‑phase clinical trials.

A substantial part of the thesis is based on experience gained from establishing two new European ²¹¹At facilities in Copenhagen (Denmark) and Jülich (Garmany). These efforts encompassed optimized cyclotron production, detection and calibration strategies, regulatory compliance, radiochemical isolation, analytical characterization, waste management and safety protocols essential for handling ²¹¹At. This work also uncovers analytical limitations of standard radio‑thin layer chromatography, and radio‑high-pressure liquid chromatography (HPLC) for astatine. HPLC with post‑column‑injection is presented and applied, enabling quantitative recovery and more reliable assessment of radiochemical conversion and purity.

A central challenge addressed in the thesis is in vivo deastatination, a barrier to clinical translation. Comparative evaluation of small‑molecule scaffolds previously suggested to stabilize the carbon–astatine bond identified structural groups capable of mitigating metabolic cleavage in mouse liver microsomes. Complementary work demonstrates that ultrasmall gold nanoparticles can form stable astatine-gold bonds, offering an alternative strategy for enhancing in vivo stability.

The thesis further investigates the radiochemistry of both electrophilic and nucleophilic ²¹¹At for labeling, purifying, and formulating diverse precursor classes, including organotin, organosilicon, organogermanium and triflate derivatives. Key findings include the necessity of antioxidant stabilizers to maintain chemical stability of ²¹¹At-labeled compounds, the evidence that deastatination is influenced by factors beyond the immediate carbon–astatine bonding environment, and identification of organogermanium precursors as highly promising to balance reactivity, synthetic accessibility, and omitting the need for protection–deprotection chemistry during astatinations. Special emphasis is given to the development of tetrazine synthons, enabling conjugation to virtually any targeting vector via trans‑cyclooctene/tetrazine ligation or direct use in pretargeting strategies. To advance clinical translation, the thesis also touches upon the current status of internal programs on PSMA‑targeting ligands and neuropeptide‑Y receptor–targeting vectors.

Taken together, this work advances the understanding of astatine chemistry, proposes stabilization principles for carbon–astatine bonds, identifies key analytical challenges, and establishes robust protocols for the safe isolation, handling, radiolabeling with ²¹¹At. Findings support ²¹¹At as a strong therapeutic complement to ¹⁸F‑based diagnostic imaging and underscore its high potential to play a transformative role in future targeted alpha radiotherapy.