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]ThIV (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.