Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation.

Abstract

To develop a radiopharmaceutical for the palliation of painful bone metastases based on the concept of bifunctional radiopharmaceuticals, we synthesized a bisphosphonate derivative labeled with rhenium-186 (186Re) that contains a hydroxyl group at the central carbon of its bisphosphonate structure, we attached a stable 186Re-MAMA chelate to the amino group of a 4-amino butylidene-bisphosphonate derivative [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-HBP) and we investigated the effect of a hydroxyl group at the central carbon of its bisphosphonate structure on affinity for hydroxyapatite and on biodistribution by conducting a comparative study with [N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) (186Re-MAMA-BP). The precursor of 186Re-MAMA-HBP, trityl (Tr)-MAMA-HBP, was obtained by coupling a Tr-MAMA derivative to 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. 186Re-MAMA-HBP was prepared by a reaction with 186ReO(4-) and SnCl2 in citrate buffer after the deprotection of the Tr groups of Tr-MAMA-HBP. After reversed-phase high-performance liquid chromatography, 186Re-MAMA-HBP had a radiochemical purity of over 95%. Compared with 186Re-MAMA-BP, 186Re-MAMA-HBP showed a greater affinity for hydroxyapatite beads in vitro and accumulated a significantly higher level in the femur in vivo. Thus, the introduction of a hydroxyl group into 186Re complex-conjugated bisphosphonates would be effective in enhancing accumulation in bones. These findings provide useful information on the design of bone-seeking therapeutic radiopharmaceuticals.

• Authors: Kazuma Ogawa, Takahiro Mukai, Yasushi Arano, Akira Otaka, Masashi Ueda, Tomoya Uehara, Yasuhiro Magata, Kazuyuki Hashimoto, Hideo Saji
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 33 Issue 4 Pg. 513-20 (May 2006) ISSN: 0969-8051 [Print] United States
• PMID: 16720243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (N-(2-((3-(3,3-diphosphonopropylcarbamoyl)propyl)-2-thioethylamino)acetyl)-2-aminoethanethiolate)oxorhenium(V)
• (N-(2-((4-((4-hydroxy-4,4-diphosphonobutyl)amino)-4-oxobutyl)-2-thioethylamino)acetyl)-2-aminoethanethiolate)oxorhenium(V)
• Diphosphonates
• Organometallic Compounds
• Durapatite

Topics

• Animals
• Diphosphonates (chemistry, pharmacokinetics, therapeutic use)
• Durapatite (metabolism)
• Femoral Neoplasms (complications, diagnostic imaging, metabolism, radiotherapy)
• Femur (diagnostic imaging, metabolism)
• Isotope Labeling (methods)
• Male
• Metabolic Clearance Rate
• Mice
• Mice, Inbred Strains
• Organ Specificity
• Organometallic Compounds (chemistry, pharmacokinetics, therapeutic use)
• Pain (etiology, prevention & control)
• Palliative Care (methods)
• Radionuclide Imaging
• Tissue Distribution