Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals

Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (Re-186-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of 186Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable Re-186-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethio- late] oxorhenium(V) (Re-186-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, Re-186-labeling was performed by reacting (ReO4-)-Re-186 with SnCl2 in citrate buffer. After purification by HPLC, Re-186-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of Re-186-MAG3-HBP and Re-186-HEDP, these Re-186 complexes were incubated in phosphate buffer. No measurable decomposition of Re-186-MAG3-HBP occurred over a 24-h period, while only approximately 30% of Re-186-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of Re-186-MAG3-HBP in bone was significantly higher than that of Re-186-HEDP. Blood clearance of Re-186-MAG3-HBP was faster than that of Re-186-HEDP. In addition, the gastric accumulation of Re-186-MAG3-HBP radioactivity was lower than that of Re-186-HEDP. In conclusion, Re-186-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.