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 (l86Re-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 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy4,4-diphosphonobutyl)carbamoylmethyllcarbamoylmethyllcarbamoylmethyllcarbamoylme thanethiolateloxorhenium(V) (l86Re-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2tritylmercaptoacetylamino)acetylaminolacetylaminolacetylaminolb utyllphosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyllglycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, 186Re- labeling was performed by reacting 186ReO4-with SnCl2 in citrate buffer. After purification by HPLC, 186Re-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of 186Re-MAG3- HBP and 186Re-HEDP, these 186Re complexes were incubated in phosphate buffer. No measurable decomposition of 186Re-MAG3-HBP occurred over a 24-h period, while only approximately 30% of 186Re_HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of 186Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower than that of 186Re-HEDP. In conclusion, 186Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.