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Toward Bifunctional Chelators for Thallium-201 for Use in Nuclear Medicine.

ABSTRACT: Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm). ²⁰¹Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked in vivo as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of ²⁰¹Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed. H₄pypa, H₅decapa, H₄neunpa-NH₂, and H₄noneunpa are multidentate N- and O-donor chelators that have previously been shown to have high affinity for ¹¹¹In, ¹⁷⁷Lu, and ⁸⁹Zr. Herein, we report the synthesis and serum stability of [^nat/201Tl]Tl³⁺ complexes with H₄pypa, H₅decapa, H₄neunpa-NH₂, and H₄noneunpa. All ligands quickly and efficiently formed complexes with [²⁰¹Tl]Tl³⁺ that gave simple single-peak radiochromatograms and showed greatly improved serum stability compared to DOTA and DTPA. [^natTl]Tl-pypa was further characterized using nuclear magnetic resonance spectroscopy (NMR), mass spectroscopy (MS), and X-ray crystallography, showing evidence of the proton-dependent presence of a nine-coordinate complex and an eight-coordinate complex with a pendant carboxylic acid group. A prostate-specific membrane antigen (PSMA)-targeting bioconjugate of H₄pypa was synthesized and radiolabeled. The uptake of [²⁰¹Tl]Tl-pypa-PSMA in DU145 PSMA-positive and PSMA-negative prostate cancer cells was evaluated in vitro and showed evidence of bioreductive release of ²⁰¹Tl and cellular uptake characteristic of unchelated [²⁰¹Tl]TlCl. SPECT/CT imaging was used to probe the in vivo biodistribution and stability of [²⁰¹Tl]Tl-pypa-PSMA. In healthy animals, [²⁰¹Tl]Tl-pypa-PSMA did not show the myocardial uptake that is characteristic of unchelated ²⁰¹Tl. In mice bearing DU145 PSMA-positive and PSMA-negative prostate cancer xenografts, the uptake of [²⁰¹Tl]Tl-pypa-PSMA in DU145 PSMA-positive tumors was higher than that in DU145 PSMA-negative tumors but insufficient for useful tumor targeting. We conclude that H₄pypa and related ligands represent an advance compared to conventional radiometal chelators such as DOTA and DTPA for Tl³⁺ chelation but do not resist dissociation for long periods in the biological environment due to vulnerability to reduction of Tl³⁺ and subsequent release of Tl⁺. However, this is the first report describing the incorporation of [²⁰¹Tl]Tl³⁺ into a chelator-peptide bioconjugate and represents a significant advance in the field of ²⁰¹Tl-based radiopharmaceuticals. The design of the next generation of chelators must include features to mitigate this susceptibility to bioreduction, which does not arise for other trivalent heavy radiometals.

SUBMITTER: Rigby A

PROVIDER: S-EPMC9305974 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAuger electron-emitting radionuclides have potential in targeted treatment of small tumors. Thallium-201 (201Tl), a gamma-emitting radionuclide used in myocardial perfusion scintigraphy, decays by electron capture, releasing around 37 Auger and Coster-Kronig electrons per decay. However, its therapeutic and toxic effects in cancer cells remain largely unexplored. Here, we assess 201Tl in vitro kinetics, radiotoxicity and potential for targeted molecular radionuclide therapy, and aim to test the hypothesis that 201Tl is radiotoxic only when internalized.MethodsBreast cancer MDA-MB-231 and prostate cancer DU145 cells were incubated with 200-8000 kBq/mL [201Tl]TlCl. Potassium concentration varied between 0 and 25 mM to modulate cellular uptake of 201Tl. Cell uptake and efflux rates of 201Tl were measured by gamma counting. Clonogenic assays were used to assess cell survival after 90 min incubation with 201Tl. Nuclear DNA damage was measured with γH2AX fluorescence imaging. Controls included untreated cells and cells treated with decayed [201Tl]TlCl.Results201Tl uptake in both cell lines reached equilibrium within 90 min and washed out exponentially (t1/2 15 min) after the radioactive medium was exchanged for fresh medium. Cellular uptake of 201Tl in DU145 cells ranged between 1.6 (25 mM potassium) and 25.9% (0 mM potassium). Colony formation by both cell lines decreased significantly as 201Tl activity in cells increased, whereas 201Tl excluded from cells by use of high potassium buffer caused no significant toxicity. Non-radioactive TlCl at comparable concentrations caused no toxicity. An estimated average 201Tl intracellular activity of 0.29 Bq/cell (DU145 cells) and 0.18 Bq/cell (MDA-MB-231 cells) during 90 min exposure time caused 90% reduction in clonogenicity. 201Tl at these levels caused on average 3.5-4.6 times more DNA damage per nucleus than control treatments.Conclusions201Tl reduces clonogenic survival and increases nuclear DNA damage only when internalized. These findings justify further development and evaluation of 201Tl therapeutic radiopharmaceuticals.

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Toward Bifunctional Chelators for Thallium-201 for Use in Nuclear Medicine.

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