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| Home > Publications database > Small molecular scaffolds toward in vivo stable Astatine-211 radiopharmaceuticals |
| Contribution to a conference proceedings/Journal Article | FZJ-2026-03772 |
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2025
Elsevier Science
Amsterdam [u.a.]
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Please use a persistent id in citations: doi:10.1016/j.nucmedbio.2025.109360
Abstract: Introduction: Due to its favorable decay properties, the α-emitter Astatine-211 (211At) is particularly promising for treatment of tumors, especially (micro-)metastases resistant to conventional β-therapy. The radionuclide has experienced increased interest, which results in an unmet need for 211At-labeled radiopharmaceuticals. Today, a major limitation in the applicability of these radiopharmaceuticals is their in vivo deastatination. Free 211At accumulates in and irradiates healthy organs, especially the thyroid and stomach, resulting in undesired off-target toxicity1. The chemical and biological mechanisms of deastatination remain unknown, but suggested explanations include the fact that the astatine-carbon bond dissociation energy is lower than for the corresponding iodine-carbon bond, the action of unidentified enzymes, and an increased sensitivity to oxidation2. Strategies developed to minimize deastatination include guanidinomethyl-functionalization, as the charged species should minimize exocytosis of radiolabeled catabolites3,4. Another strategy applies the neopentyl glycol motif, emphasizing a crucial role of the OH groups in compound stabilization towards CYP-mediated metabolism5. Recently, neighboring substituents have been shown improve in vivo stability6. Here, we describe the design, synthesis, and comparison of 211At-labeled small molecular scaffolds to elucidate mechanisms of and find solutions to overcome in vivo 211At-deastatination. Methods: The library of scaffolds was selected and synthesized based on literature to combine functionalities of different properties, hypothesizing 211At-stabilization by electronic, steric and/or polarization factors. Aromatic and aliphatic 211At-labeling was achieved by demetallation of organotin, organosilicon or organogermanium precursors7 under oxidizing conditions or nucleophilic substitution of triflate precursors, respectively5. The 211At- labeled compounds were characterized by radioTLC and radioHPLC using non-radioactive iodinated surrogate compounds as reference and astatine recovery was quantified via post-column injection8. Tracers were isolated by HPLC and reformulated in buffer/ascorbic acid. Metabolic deastatination was assessed in mouse liver microsome stability assays. Results: Six small molecular scaffold precursors as well as the corresponding iodine references have been synthesized. Structures of the 211At-labeled compounds are presented in Figure 1A, as well as their radiolabeling characteristics. Optimization of the labeling and purification protocols is ongoing. Post-column injection chromatograms of purified compounds 5 and 6 are shown in Figure 1B. Addition of an antioxidant is mandatory for chemical stability, and we showed that 0.5% ascorbic acid is sufficient to stabilize the compounds and does not interfere with the microsome metabolic performance. Preliminary microsome stability data (Figure 1C) showed >97% stability of compound 6 over 4h, while significant metabolization was observed for positive control diclofenac. Including negative controls in which microsomes and NADH was omitted, respectively, recovery were >92%. Conclusions: In this study, we synthesized and radiolabeled several small molecular scaffolds reported to stabilize 211At. Preliminary results from a mouse microsome assay indicate stability of compound 6, while evaluation of compound 1-5 is ongoing. Based on these findings, the most promising stabilized lead scaffolds are to be evaluated in vivo in rodents in the near future. Aiding the development of new 211At-labeled radiopharmaceuticals, the aim is to expand the scaffold library, after which a synthon of the lead scaffold will be developed, which can be conveniently conjugated to targeting vectors of interest.
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