Toward Bifunctional Chelators for Thallium-201 for Use in Nuclear Medicine Article Swipe
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· 2022
· Open Access
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· DOI: https://doi.org/10.1021/acs.bioconjchem.2c00284
· OA: W4284896194
Auger electron therapy exploits the cytotoxicity of low-energy electrons emitted during radioactive decay that travel very short distances (typically <1 μm). <sup>201</sup>Tl, with a half-life of 73 h, emits ∼37 Auger and other secondary electrons per decay and can be tracked <i>in vivo</i> as its gamma emissions enable SPECT imaging. Despite the useful nuclear properties of <sup>201</sup>Tl, satisfactory bifunctional chelators to incorporate it into bioconjugates for molecular targeting have not been developed. H<sub>4</sub>pypa, H<sub>5</sub>decapa, H<sub>4</sub>neunpa-NH<sub>2</sub>, and H<sub>4</sub>noneunpa are multidentate N- and O-donor chelators that have previously been shown to have high affinity for <sup>111</sup>In, <sup>177</sup>Lu, and <sup>89</sup>Zr. Herein, we report the synthesis and serum stability of [<sup>nat/201</sup>Tl]Tl<sup>3+</sup> complexes with H<sub>4</sub>pypa, H<sub>5</sub>decapa, H<sub>4</sub>neunpa-NH<sub>2</sub>, and H<sub>4</sub>noneunpa. All ligands quickly and efficiently formed complexes with [<sup>201</sup>Tl]Tl<sup>3+</sup> that gave simple single-peak radiochromatograms and showed greatly improved serum stability compared to DOTA and DTPA. [<sup>nat</sup>Tl]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 H<sub>4</sub>pypa was synthesized and radiolabeled. The uptake of [<sup>201</sup>Tl]Tl-pypa-PSMA in DU145 PSMA-positive and PSMA-negative prostate cancer cells was evaluated <i>in vitro</i> and showed evidence of bioreductive release of <sup>201</sup>Tl and cellular uptake characteristic of unchelated [<sup>201</sup>Tl]TlCl. SPECT/CT imaging was used to probe the <i>in vivo</i> biodistribution and stability of [<sup>201</sup>Tl]Tl-pypa-PSMA. In healthy animals, [<sup>201</sup>Tl]Tl-pypa-PSMA did not show the myocardial uptake that is characteristic of unchelated <sup>201</sup>Tl. In mice bearing DU145 PSMA-positive and PSMA-negative prostate cancer xenografts, the uptake of [<sup>201</sup>Tl]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 H<sub>4</sub>pypa and related ligands represent an advance compared to conventional radiometal chelators such as DOTA and DTPA for Tl<sup>3+</sup> chelation but do not resist dissociation for long periods in the biological environment due to vulnerability to reduction of Tl<sup>3+</sup> and subsequent release of Tl<sup>+</sup>. However, this is the first report describing the incorporation of [<sup>201</sup>Tl]Tl<sup>3+</sup> into a chelator-peptide bioconjugate and represents a significant advance in the field of <sup>201</sup>Tl-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.
