Background

[PubMed]

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBPs) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds have a very high affinity for hydroxyapatite (HA), a component of the bone matrix. These phosphonates or their derivatives tend to accumulate in osteoclasts located at areas of increased bone metabolism by inhibiting the enzyme farnesyl diphosphate (or pyrophosphate) synthase, an important regulatory enzyme of the cellular mevalonate pathway, which is involved in protein prenylation (1). The molecular mechanism of action of BPs and the NBPs has been described by Drake et. al. (2). Several BPs and NBPs are commercially available for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with ^99mTc or ^186/188Re and used for the imaging and treatment of pain as a result of bone metastases from cancer such as that of the breast or the prostate (3). However, these compounds have limited efficacy primarily because they exist either as a mixture of anionic compounds with varying properties (e.g., ^99mTc- labeled methyl diphosphonate (MDP)) or are unstable (e.g., ⁸⁶Re-labeled 1-hydroxyethylidene-1,1-diphosphonate) under in vivo conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue such as the gastric lining of the stomach (4). The limited clinical utility of radiolabeled BPs was suggested to be caused by the dual activities exhibited by the compounds: one phosphonate group acts as a radionuclide chelator, and the other phosphonate group binds to the target(s).Therefore, due to the close proximity of the two groups, one activity may be interfering with the other (4).

In an effort to solve the stability problems observed with the ¹⁸⁶Re-labeled NBPs, Ogawa et al. developed two new NBPs, ¹⁸⁶Re-[N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-aminoethylenethiolate] oxorhenium (V) ([¹⁸⁶Re]MAMA-BP) and its hydroxylated derivative, ¹⁸⁶Re-[N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethanethiolate] oxorhenium (V) ([¹⁸⁶Re]MAMA-HBP) (3). The investigators then compared the two compounds for their affinity to HA under in vitro conditions and studied the biodistribution of the radiochemicals in normal mice. This chapter presents the results obtained with [¹⁸⁶Re]MAMA-BP. Results obtained with [¹⁸⁶Re]MAMA-HBP are presented in a separate chapter of MICAD (5).

Synthesis

[PubMed]

A ¹⁸⁶Re-glucoheptonate ligand exchange reaction was used for the synthesis of [¹⁸⁶Re]MAMA-BP and ¹⁸⁶Re-1-hydroxyethylidene-1,1-diphosphonate ([¹⁸⁶Re]-MAMA-HEDP; used as a control in the various studies) and is detailed elsewhere (6). The radiochemical yield of [¹⁸⁶Re]MAMA-BP was reported to be between 21.3 ± 4.5 and 32.0 ± 4.1% with a purity of 96.4 ± 1.4%. Specific activity of the radiolabeled compounds was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

The in vitro stability of [¹⁸⁶Re]MAMA-BP after a 24-h incubation in 0.1 M phosphate-buffered saline (pH, 7.0) saturated with 95% O₂ and 5% CO₂ at 37°C was reported to be 81.8 ± 1.7% as determined with reversed-phase high-performance liquid chromatography or thin-layer chromatography. Under the same conditions, the stability of [¹⁸⁶Re]MAMA-HBP was reported to be 75.55 ± 1.57%.

The HA binding of [¹⁸⁶Re]MAMA-BP was determined by using different amounts (1–25 mg/mL) of commercially available HA beads suspended in Tris/HCl-buffered saline (pH, 7.4) as described by Ogawa et al. (3). The percent of HA binding was determined with an equation given elsewhere (3). Approximately 40% of [¹⁸⁶Re]MAMA-BP bound to the HA beads at the lowest concentration (compared with ~70% for [¹⁸⁶Re]MAMA-HBP) and increased to ~95.0% at the highest concentration (compared with ~97.5% for [¹⁸⁶Re]MAMA-HBP). Results from this study indicated that [¹⁸⁶Re]MAMA-HBP had a higher affinity for HA than [¹⁸⁶Re]MAMA-BP.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

Supplemental Information

[Disclaimers]

No information is currently available.

References

1.

Kimmel D.B. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res. 2007;86(11):1022–33. [PubMed: 17959891]

2.

Drake M.T., Clarke B.L., Khosla S. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83(9):1032–45. [PMC free article: PMC2667901] [PubMed: 18775204]

3.

Ogawa K., Mukai T., Arano Y., Otaka A., Ueda M., Uehara T., Magata Y., Hashimoto K., Saji H. Rhemium-186-monoaminemonoamidedithiol-conjugated bisphosphonate derivatives for bone pain palliation. Nucl Med Biol. 2006;33(4):513–20. [PubMed: 16720243]

4.

Torres Martin de Rosales R., Finucane C., Mather S.J., Blower P.J. Bifunctional bisphosphonate complexes for the diagnosis and therapy of bone metastases. Chem Commun (Camb). 2009;(32):4847–9. [PMC free article: PMC7116767] [PubMed: 19652801]

5.

Chopra, A., 186Re-Labeled [N-2[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]acetyl]-2-aminoethylenethiolate] conjugated to hydroxyl-bisphosphonate. Molecular Imaging and Contrast agent Database (MICAD) [database online]. National Library of Medicine, NCBI, Bethesda, MD, USA. Available from www​.micad.nih.gov, 2004 -to current.

6.

Ogawa K., Mukai T., Arano Y., Hanaoka H., Hashimoto K., Nishimura H., Saji H. Design of a radiopharmaceutical for the pallation of painful bone metastases: rhenium-186-labeled bisphosphonate derivative. J. Label. Compd. Radiopharm. 2004;47:753–761.