Purpose <p>Ovarian cancer (OC) is frequently diagnosed at late stages after metastasis and chemorefractive leading to poor survival outcomes. There is a critical need for earlier detection and novel antigen-targeted therapies to improve patient survival at all stages. TROP-2 is a transmembrane glycoprotein overexpressed in many cancers and presents a promising target for OC. Recently, antibody-drug conjugates such as sacituzumab govitecan (SG) and datopotamab deruxtecan have been approved for various TROP-2-positive malignancies such as metastatic breast, lung, or urothelial cancer. However, diagnosis is based on prior therapy failure and TROP-2 therapy focused on antibody-drug conjugates.</p> Methods <p>Minimal radiotheranostic versions of SG were developed for immunoPET imaging with [⁸⁹Zr]Zr-DFO-SG in flank and intraperitoneal OVCAR3 implants. IHC was also done to identify other OC models that express Trop2. Radiotherapy variants of SG [¹⁷⁷Lu]Lu-DTPA-SG, [²²⁵Ac]Ac-mcp-Direct-SG, or [²²⁵Ac]Ac-mcp-Click-SG were also made and tested for efficacy alongside the standard of care SG.</p> Results <p>[¹⁷⁷Lu]Lu-DTPA-SG delayed tumor recurrence for up 6–8 weeks post-treatment and retreatment prolonged overall survival to 21 weeks matching standard of care SG dosing. Between two linkers, [²²⁵Ac]Ac-mcp-Direct-SG was found to yield a superior minimal conjugation of SG than [²²⁵Ac]Ac-mcp-Click-SG, with better tumor targeting by biodistribution and prolonged reduction in OC over 30 weeks.</p> Conclusion <p>Ultimately, utility of SG was improved through minimal modification of the ADC and applied a “treat what you see” approach to TROP-2-positive OC. By using a new tetrafluorophenyl linkage of macropa, [²²⁵Ac]Ac-mcp-Direct-SG greatly reduced tumor burden in OC with most mice surviving and tolerating the therapy.</p>