Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates

(211)At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C−At “organometalloid” bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 × 10(6) faster at 37 °C than the oxidative deiodination one. Therefore, we attribute the “internal” deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes.