Development of a Rhenium-186-Labeled MAG3-Conjugated Bisphosphonate for the Palliation of Metastatic Bone Pain Based on the Concept of Bifunctional Radiopharmaceuticals

摘要

Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate(~(186)Re-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 ~(186)Re-HEDP in vivo.In this study,on the basis of the concept of bifunctional radiopharmaceuticals,we designed a stable ~(186)Re-mercaptoacetylglycylglycylglycine(MAGS)complex-conjugated bisphosphonate,[[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethio-late]oxorhenium(V)(~(186)Re-MAG3-HBP).As a precursor,[l-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)acetyljglycylglycylglycine(Tr-MAG3)with the bisphosphonate analogue.After deprotection of the trityl group of Tr-MAG3-HBP,~(186)Relabeling was performed by reacting ~(186)ReO_4~-with SnCl2 in citrate buffer.After purification by HPLC,~(186)Re-MAG3-HBP showed a radiochemical purity of over 95%.To compare the stability of ~(186)Re-MAG3-HBP and ~(186)Re-HEDP,these ~(186)Re complexes were incubated in phosphate buffer.No measurable decomposition of ~(186)Re-MAG3-HBP occurred over a 24-h period,while only approximately 30% of ~(186)Re-HEDP remained intact 24 h postincubation.In biodistribution experiments,the radioactivity level of ~(186)Re-MAG3-HBP in bone was significantly higher than that of ~(186)Re-HEDP.Blood clearance of ~(186)Re-MAG3-HBP was faster than that of ~(186)Re-HEDP.In addition,the gastric accumulation of ~(186)Re-MAG3-HBP radioactivity was lower than that of ~(186)Re-HEDP.In conclusion,~(186)Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.