188Re(CO)3-Dipicolylamine-Alendronate: A New Bisphosphonate Conjugate for the Radiotherapy of Bone Metastases

The palliation of pain due to bone metastases using targeted compounds containing β-emitters such as rhenium-188 (188Re) is an accepted and effective form of treatment. Here, we describe the efficient synthesis and preclinical evaluation of 188Re(CO)3-dipicolylamine(DPA)-alendronate, a novel bifunctional bisphosphonate for the palliative treatment of bone metastases. 188Re(CO)3-DPA-alendronate can be easily synthesized with high specific activities and yields (18.8 GBq/mg, radiochemical yield ≥96%) in two steps using kit-based methodology, and in contrast with the clinically approved bisphosphonate 186/188Re-HEDP, it forms inert, single species that have been well-characterized. In vivo imaging and biodistribution studies demonstrate that 188Re(CO)3-DPA-alendronate is superior to 188Re-HEDP in targeting and accumulating in areas of high metabolic bone activity while having low soft-tissue uptake. In addition to these studies, a simple and convenient new method for purifying its precursor, fac-[188Re(CO)3(H2O)3]+, is described.