Theranostic Agent Targeting Bone Metastasis: A Novel [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTA-HBED-bisphosphonate

Bone metastasis in cancer patients is a major disease advancement for various types of cancer. Previously, [⁶⁸Ga]Ga-HBED-CC-bisphosphonate ([⁶⁸Ga]Ga-P15-041) showed excellent bone uptake and efficient detection of bone metastasis in patients. To accommodate different α- or β^--emitting metals for radionuclide therapy, a novel DOTA-HBED-CC-bisphosphonate (P15-073, 1) was prepared and the corresponding [⁶⁸Ga]Ga-1 and [¹⁷⁷Lu]Lu-1 were successfully synthesized in high yields and purity. Gallium-68 conjugation to HBED-CC at room temperature and lutetium-177 conjugation to DOTA at 95 °C were verified in model compounds through secondary mass confirmation. These bisphosphonates, [⁶⁸Ga]Ga-1 and [¹⁷⁷Lu]Lu-1, displayed high binding affinity to hydroxyapatite in vitro. After an iv injection, it showed excellent uptake in the spine of normal mice, and micro-PET/CT imaging of nude mice model of bone metastasis showed high bone uptake in tumor tissue. The results indicated that [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-1 holds promise as a theranostic radioligand agent for managing cancer bone metastases.