Synthesis and Evaluation of a Bifunctional Chelator for Thorium-227 Targeted Radiotherapy

Thorium-227 (²²⁷Th) is an α-emitting radionuclide currently under investigation for targeted alpha therapy. Available chelators used for this isotope suffer from challenging multistep syntheses. Here, we present the synthesis and preclinical evaluation of a novel bifunctional chelator, p-SCN-Bn-DOTHOPO, which contains an isothiocyanate group that is suitable for conjugation to biological molecules. This bifunctional chelator was prepared with a 26% overall yield in four steps and conjugated to the human epidermal growth factor receptor 2 targeting antibody, trastuzumab. The resulting immunoconjugate was labeled with [²²⁷Th]Th^IV (pH 5.5, room temperature, 60 min) with ≥95% radiochemical yield and purity. The conjugate was also labeled with zirconium-89 (⁸⁹Zr), which can be used for positron emission tomography imaging. The radiometal complexes were subsequently investigated for their biological stability. The results described here provide insight into ligand design strategies and optimization of chelators for the development of the next generation of ⁸⁹Zr and ²²⁷Th radiopharmaceuticals.