Targeted Auger electron-emitter therapy: Radiochemical approaches for thallium-201 radiopharmaceuticals

Introduction: Thallium-201 is a radionuclide that has previously been used clinically for myocardial perfusion scintigraphy. Although in this role it has now been largely replaced by technetium-99 m radiopharmaceuticals, thallium-201 remains attractive in the context of molecular radionuclide therapy for cancer micrometastases or single circulating tumour cells. This is due to its Auger electron (AE) emissions, which are amongst the highest in total energy and number per decay for AE-emitters. Currently, chemical platforms to achieve this potential through developing thallium-201-labelled targeted radiopharmaceuticals are not available. Here, we describe convenient methods to oxidise [Tl-201]Tl(I) to chelatable [Tl-201]Tl(III) and identify challenges in stable chelation of thallium to support future synthesis of effective [Tl-201]-labelled radiopharmaceuticals. Methods: A plasmid pBR322 assay was carried out to determine the DNA damaging properties of [Tl-201]Tl(III). A range of oxidising agents (ozone, oxygen, hydrogen peroxide, chloramine-T, iodogen, iodobeads, trichloroisocyanuric acid) and conditions (acidity, temperature) were assessed using thin layer chromatography. Chelators EDTA, DTPA and DOTA were investigated for their [Tl-201]Tl(III) radiolabelling efficacy and complex stability. Results: Isolated plasmid studies demonstrated that [Tl-201]Tl(III) can induce single and double-stranded DNA breaks. Iodo-beads, iodogen and trichloroisocyanuric acid enabled more than 95% conversion from [Tl-201]Tl (I) to [Tl-201]Tl(III) under conditions compatible with future biomolecule radiolabelling (mild pH, room temperature and post-oxidation removal of oxidising agent). Although chelation of [Tl-201]Tl(III) was possible with EDTA, DTPA and DOTA, only radiolabeled DOTA showed good stability in serum. Conclusions: Decay of [Tl-201]Tl(III) in proximity to DNA causes DNA damage. Iodobeads provide a simple, mild method to convert thallium-201 from a 1+ to 3+ oxidation state and [Tl-201]Tl(III) can be chelated by DOTA withmoderate stability. Of thewell-established chelators evaluated, DOTA ismost promising for future molecular radionuclide therapy using thallium-201; nevertheless, a new generation of chelating agents offering resistance to reduction and dissociation of [Tl-201]Tl(III) complexes is required. (C) 2021 The Author(s). Published by Elsevier Inc.

Automated summary

Thallium-201 is attractive for molecular radionuclide therapy due to its Auger electron emissions, but chemical platforms for developing targeted radiopharmaceuticals are currently unavailable. Oxidation of [Tl-201]Tl(I) to chelatable [Tl-201]Tl(III) and challenges in stable chelation of thallium were investigated to support future synthesis of effective [Tl-201]-labelled radiopharmaceuticals.