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

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 [²⁰¹Tl]Tl(I) to chelatable [²⁰¹Tl]Tl(III) and identify challenges in stable chelation of thallium to support future synthesis of effective [²⁰¹Tl]-labelled radiopharmaceuticals.

A plasmid pBR322 assay was carried out to determine the DNA damaging properties of [²⁰¹Tl]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 [²⁰¹Tl]Tl(III) radiolabelling efficacy and complex stability.

Isolated plasmid studies demonstrated that [²⁰¹Tl]Tl(III) can induce single and double-stranded DNA breaks. Iodo-beads, iodogen and trichloroisocyanuric acid enabled more than 95% conversion from [²⁰¹Tl]Tl(I) to [²⁰¹Tl]Tl(III) under conditions compatible with future biomolecule radiolabelling (mild pH, room temperature and post-oxidation removal of oxidising agent). Although chelation of [²⁰¹Tl]Tl(III) was possible with EDTA, DTPA and DOTA, only radiolabeled DOTA showed good stability in serum.

Decay of [²⁰¹Tl]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 [²⁰¹Tl]Tl(III) can be chelated by DOTA with moderate stability. Of the well-established chelators evaluated, DOTA is most promising for future molecular radionuclide therapy using thallium-201; nevertheless, a new generation of chelating agents offering resistance to reduction and dissociation of [²⁰¹Tl]Tl(III) complexes is required.