Abstract
211At 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 × 106 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.
Highlights
Halogens are usually named according to ancient Greek words denoting one of their characteristics
One should note that oxidative dehalogenation induced by TBHP occurs at physiological pH, i.e. 7.4, with similar kinetics as observed at pH = 4.7
We report the first experiments of astatobenzoate dehalogenations, and shed light on the probable in vivo mechanism by which these therapeutically relevant compounds are catabolized
Summary
Halogens are usually named according to ancient Greek words denoting one of their characteristics. The slow mAbs pharmacokinetics are not well-suited to be combined with the 211At half-life time[7, 16], and astatine-labelled antibodies have been so far limited to locoregional treatments This behaviour is remarkable, as it echoes the one of proteins, iodinated through direct labelling or using the Bolton-Hunter reagent[17]. One may argue that since astatine is absent from the biosphere (it is the rarest naturally occurring element on Earth)[28, 29], no At-specific enzyme that catalyses C−At bond breakages is likely to exist Some proteins such as the sodium-iodide symporter recognize both astatide and iodide[30, 31], demonstrating that the presence of iodine-processing enzymes may affect astatine compounds. The second and most often quoted justification, that the C−At bonds are weaker than the corresponding C−I ones, true[32], is not sufficient to explain why astatobenzoate-labelled proteins are seemingly stable in blood and not when internalized inside living cells
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