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

Abstract

Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-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 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate]oxorhenium(V) (186Re-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, 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 (186)Re 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 (186)Re-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.

• Authors: Kazuma Ogawa, Takahiro Mukai, Yasushi Arano, Masahiro Ono, Hirofumi Hanaoka, Seigo Ishino, Kazuyuki Hashimoto, Hiroshi Nishimura, Hideo Saji
• Journal: Bioconjugate chemistry (Bioconjug Chem) 2005 Jul-Aug Vol. 16 Issue 4 Pg. 751-7 ISSN: 1043-1802 [Print] United States
• PMID: 16029015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diphosphonates
• Oligopeptides
• Organometallic Compounds
• Radiopharmaceuticals
• rhenium-mercaptoacetyltriglycine
• Rhenium

Topics

• Bone Neoplasms (radiotherapy, secondary)
• Diphosphonates (chemistry, therapeutic use)
• Humans
• Magnetic Resonance Spectroscopy
• Oligopeptides (chemistry, therapeutic use)
• Organometallic Compounds (chemistry, therapeutic use)
• Radiopharmaceuticals (therapeutic use)
• Rhenium (chemistry, therapeutic use)
• Spectrometry, Mass, Fast Atom Bombardment