Background

[PubMed]

Cancers such as those of the breast, prostate, kidney, and thyroid have a high incidence of metastases, particularly in the bone, which results in bone resorption, pain, hypercalcemia, spinal compression, decreased mobility, and even fractures (1). In addition, osteoporosis (bone resorption), a common condition experienced most frequently by menopausal women as well as aging women and men, often leads to bone fractures in these individuals (2). Although chemo- and radiotherapy are often used to treat bone metastases, none of these treatments control the progression of this disease or result in a better prognosis for the patient. Bisphosponates (BPs) or their nitrogen-containing derivatives (N-BPs) are the most commonly used compounds for the selective targeting and treatment of bone-related ailments observed during cancer metastases or osteoporosis (3, 4) because of their attraction to hydroxyapatite, a major component of bone, and because they alleviate, to some extent, the symptoms and complications arising from these conditions. The chemical structure, characteristics, and pharmacological behavior of BPs has been described by Hirabayashi and Fujisaki (3). Briefly, the parent BP compound contains a characteristic phosphate-carbon-phosphate (P-C-P) bond that is resistant to enzymatic digestion and has no substitution at the central carbon (5); N-BPs, however, have a nitrogen-containing moiety substituted on the carbon atom (6). BPs and N-BPs were shown to inhibit bone-related events by different mechanisms (7), and N-BPs were reported to be 100- to 10,000-fold more potent than BPs (8). BPs and N-BPs are approved by the United States Food and Drug Administration for the treatment of bone diseases such as osteoporosis, Paget’s disease of the bone, hypercalcemia, and bone metastases. In addition, these drugs also being evaluated in clinical trials for the treatment and imaging of different bone-related disorders.

Accurate and early noninvasive detection of osteoporosis or bone metastases can assist in the development of a suitable treatment strategy and possibly improve the prognosis for a patient. Radiolabeled BPs, such as methyl diphosphonate (MDP) (9), hydroxymethylene diphosphonate, 1-hydroxyethylene diphosphonate, etc., are often used as imaging agents for the detection of bone remodeling (e.g., during cancer metastases) or repair (e.g., after a fracture) because these compounds tend to accumulate in osteoclasts at active bone sites (10). Although radiolabeled N-BPs have been used for the therapy of bone cancer in animal models (11) and humans (12), no N-BPs have been used for bone imaging. Panwar et al. (13) synthesized a ^99mTc-labeled multidentated N-BP, 5-amino-1,3-bis(ethylamine-(N,N-dimethyl phosphonic acid)acetamido)benzene (or 5-aminoisophthalate tetramethylene phosphonic acid (^99mTc-IPTMP)) and investigated its biodistribution in mice. The accumulation of ^99mTc-IPTMP in select organs of the animals was compared to that of the same organs obtained from animals treated with ^99mTc-MDP. Whole-body scintigraphic imaging of rabbits treated with the radiolabeled compound was also performed by the investigators.

Synthesis

[PubMed]

The chemical synthesis of IPTMP was described in detail by Panwar et al. (13). The final yield of the tetraphosphonate compound was reported to be 89% with a purity of >97%.

The labeling of IPTMP with ^99mTc was done in the presence of tin at a pH between 6.0 and 6.5 in 0.5 M sodium bicarbonate for 30 min at room temperature (13). The yield of ^99mTc-IPTMP was reported to be >97% with a radiochemical purity of >97% as determined with instant thin-layer paper chromatography–silica gel (ITLC-SC). The Rf of ^99mTc-IPTMP on ITLC-SC was 0.3, which indicates that only one species of the labeled compound was formed during the labeling process. The specific activity of the radiochemical was not reported.

The synthesis and specific activity of ^99mTc-MDP used for some studies were not reported (13).

The transchelation of ^99mTc from labeled MDP and IPTMP was investigated in the presence of 25–100 mM diethylenetriamine-pentaacetic acid (DTPA) (13). The transchelation of ^99mTc from labeled MDP increased with the concentration of DTPA to a maximum of 45%, but for ^99mTc-IPTMP the transchelation was reported to be 6% at all concentrations of DTPA.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

^99mTc-IPTMP was reported to be stable in human serum for up to 24 h under in vitro physiological conditions, similar to ^99mTc-MDP, and no transchelation of serum proteins was observed as determined by ITLC-SC (13).

Animal Studies

Human Studies

[PubMed]

No references are currently available.

Supplemental Information

[Disclaimer]

No information is currently available.

References

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Kennel K.A., Drake M.T. Adverse effects of bisphosphonates: implications for osteoporosis management. Mayo Clin Proc. 2009;84(7):632–7. [PMC free article: PMC2704135] [PubMed: 19567717]

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Chopra, A., 99mTc-Methyl diphosphonate. 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.

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Arano Y. Recent advances in 99mTc radiopharmaceuticals. Ann Nucl Med. 2002;16(2):79–93. [PubMed: 12043913]

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Essman S.C., Lewis M.R., Miller W.H. Intraorgan biodistribution and dosimetry of 153Sm-ethylenediaminetetramethylene phosphonate in juvenile rabbit tibia: implications for targeted radiotherapy of osteosarcoma. J Nucl Med. 2005;46(12):2076–82. [PubMed: 16330573]

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Park I.H., Ro J., Nam B.H., Kwon Y., Lee K.S. Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases. BMC Cancer. 2009;9:154. [PMC free article: PMC2694816] [PubMed: 19454038]

13.

Panwar P., Singh S., Kumar N., Rawat H., Mishra A.K. Synthesis, characterization, and in vivo skeletal localization of a new (99m)Tc-based multidentate phosphonate chelate: 5-Amino-1,3-bis(ethylamine-(N,N dimethyl diphosphonic acid) acetamido) benzene. Bioorg Med Chem. 2007;15(2):1138–45. [PubMed: 17088066]

This MICAD chapter is not included in the Open Access Subset, because it was authored / co-authored by one or more investigators who was not a member of the MICAD staff.