Chelating [²²⁷Th]Th⁴⁺ for Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors

Targeted alpha therapy (TAT) has shown high promise for the effective treatment of advanced stage cancers. Of the proposed radionuclides for TAT, Thorium-227 represents an interesting candidate given its relatively long half-life, 18.7 days, and the cascade of short-lived, high-potency, alpha-emitting daughter progeny in its decay scheme. However, to date few chelators exist which can effectively and stably bind [²²⁷Th]Th⁴⁺ at molar activities high enough for TAT. To address this challenge, this study investigated various chelating ligands for coordination of [²²⁷Th]Th⁴⁺. H₄noneunpaX was identified as a promising chelator, demonstrating radiolabeling with [²²⁷Th]Th⁴⁺ at concentrations of 10^-6 M (A_m = 272 kBq/nmol). The coordination characteristics of [Th(noneunpaX)] have been investigated through ¹H NMR spectroscopy, mass spectrometry, and DFT calculations. In this study, we also investigate for the first time the pairing of Th-227 with a peptide-based bioconjugate and evaluate the <i>in vivo</i> biodistribution characteristics. [²²⁷Th]Th-nonenupaX-Ahx-Tyr³-TATE was prepared under mild conditions (ambient temperature, 30 min) and evaluated in NRG mice bearing AR42J xenografts as a model for pancreatic neuroendocrine tumors. The ²²⁷Th-labeled radiopeptide showed high uptake in tumors (25.8±6.2 %IA/g at 3 h p.i.) and low uptake in non-targeted organs. Although some release of Th-227 was noted in serum stability studies this was not observed <i>in vivo</i>. This ligand architecture serves as an interesting framework for future optimization, which will involve improvements to the overall stability by enhancing the rigidity of the backbone and assessing other pendent donor groups with a stronger affinity toward [²²⁷Th]Th⁴⁺. Overall, this study demonstrated for the first time the viability of using peptide-based targeting to effectively deliver Th-227 to tumor sites.