The 3,4,3-(LI-1,2-HOPO) ligand was identified for improved stability of 89Zr chelation and the bifunctional p-SCN-Bn-HOPO was developed for improved radioimmunoPET imaging using 89Zr.1 Originally developed as a sequestration agent to remove actinides from biological systems, the HOPO ligand also possesses potential for chelating therapeutic radioisotopes. Stable chelation of both 89Zr and therapeutic radioisotopes would position HOPO as a theranostic chelator and thus facilitate clinical translation. The ligands HOPO and DOTA were radiolabeled with 177Lu or 225Ac to afford &gt;95% radiochemically pure conjugates at room temperature for 15 min (Lu) or 50°C for 1 h (Ac). In vitro assessment of the stability of 177Lu-HOPO was determined in human serum, cell media, metal cation solutions (Cu2+, Fe3+, Gd3+, Ga3+), and in EDTA solutions, relative to 177Lu-DOTA. These studies indicate that the 177Lu-HOPO complex is stable in biological media, but slightly less stable than the 177Lu-DOTA complex with high EDTA, Gd3+, or Cu2+ concentrations. The stability of the DOTA and HOPO complexes with both 177Lu and 225Ac were determined in healthy, nude female mice. The results indicate that the 177Lu-HOPO complex was as stable in vivo as the DOTA complex, but the 225Ac-HOPO complex was not. These data are consistent with stability constant data for +3 lanthanide’s and actinides reported by Abergel.2 The bifunctional p-SCN-Bn-HOPO was then used to synthesize a 177Lu-HOPO-trastuzumab radioimmunoconjugate. This construct was found to be stable in human serum, maintained immunogenicity, and demonstrated low bone uptake (~3% ID/g in both healthy and tumor-bearing animals at 7 d p.i.) and good tumor retention in the SKOV-3 tumors (25 ± 6 %ID/g at 7 d p.i.). The HOPO -antibody construct appears to be appropriate for delivering 177Lu to tumor sites. This suggests that HOPO- antibody constructs may be used for PET imaging (89Zr), and radiotherapy (177Lu). This study indicates that the HOPO-conjugated antibody could be synthesized, characterized, and approved for use with both metals for PET and radiotherapy, rather than multiple chelator-conjugated antibodies for each metal.

Evaluation of 3,4,3-(LI-1,2-HOPO) and p-SCN-Bn-HOPO for use in radiotherapeutics as a chelator for 177Lu and 225Ac

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.