Development of [⁹⁰Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

Introduction: Based on the concept of bifunctional radiopharmaceuticals, we have previously developed ¹⁸⁶Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed ⁹⁰Y-labeled radiopharmaceutical could be developed. Methods: In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [⁹⁰Y]DOTA-complex-conjugated bisphosphonate ([⁹⁰Y]DOTA-HBP) was prepared by coordination with ⁹⁰Y, and its biodistribution was studied in comparison to [⁹⁰Y]citrate. Results: In biodistribution experiments, [⁹⁰Y]DOTA-HBP and [⁹⁰Y]citrate rapidly accumulated and resided in the bone. Although [⁹⁰Y]citrate showed a higher level of accumulation in the bone than [⁹⁰Y]DOTA-HBP, the clearances of [⁹⁰Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [⁹⁰Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [⁹⁰Y]DOTA-HBP were lower than those of [⁹⁰Y]citrate. Conclusions: [⁹⁰Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [⁹⁰Y]citrate. Since the DOTA ligand forms a stable complex not only with ⁹⁰Y but also with lutetium (¹⁷⁷Lu), indium (¹¹¹In), gallium (^67/68Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging.