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. Because of their attraction to hydroxyapatite, a major component of bone, 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). The chemical structure, characteristics, and pharmacological behavior of BPs and their derivatives have 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 have been 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). Both 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 are 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 animals (11) and humans (12), no N-BPs have been evaluated or used for bone imaging. Panwar et al. (13) synthesized a 99mTc-labeled multidentated N-BP, trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid (99mTc-CDTMP) and investigated its biodistribution in mice. The investigators also compared the whole-body scintigraphic images of rabbits treated with 99mTc-CDTMP with those obtained after treatment with 99mTc-MDP. In addition, imaging with 99mTc-CDTMP was performed on cancer patients with bone metastases, and the ratios of radioactivity accumulated in the bone lesion to soft tissue and the normal bone were determined.
Other sources of information
Protein and mRNA sequence of human farnesyl diphosphate synthase
Gene information regarding human farnesyl diphosphate synthase (GeneID: 2224)
Farnesyl diphosphate synthase in Online Mendelian Inheritance in Man (OMIM)
Structure of farnesyl diphosphate synthase complexed with a bisphosphonate
Farnesyl diphosphate synthase in Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways
Related chapters in MICAD
The chemical synthesis of CDTMP was done as described by Panwar et al. (13). The formation of CDTMP was confirmed with nuclear magnetic resonance spectroscopy, and the final yield of the compound was 92%.
The synthesis and specific activity of 99mTc-MDP used for some studies were not reported (13).
The labeling of CDTMP 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-CDTMP 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-CDTMP on ITLC-SC was reported to be 0.3, which suggests that only one species of the labeled compound was formed during the labeling process. The specific activity of the radiochemical was not reported.
In Vitro Studies: Testing in Cells and Tissues
99mTc-CDTMP was reported to be stable in human serum for up to 24 h under in vitro physiological conditions (13). Only 3% of the radioisotope was reported to be detached from the labeled compound during this period as determined with ITLC-SC.
Panwar et al. investigated the biodistribution of 99mTc-CDTMP in BALB/c mice (13). The animals (n = 5 mice/time point) were injected with the radiochemical through the tail vein and euthanized at predetermined intervals varying from 1 h to 24 h after treatment. Major organs of the animals were subsequently removed, and the incorporated radioactivity in each organ was determined (data were presented as percent injected dose/gram tissue ± standard deviation (% ID/g ± SD)). Maximum accumulation of 99mTc-CDTMP was observed in the bones of the animals (7.69 ± 0.65% ID/g at 1 h, 6.93 ± 0.36% ID/g at 4 h, and 6.22 ± 0.18% ID/g at 24 h), followed by the kidneys (1.04 ± 0.05% ID/g at 1 h, 1.52% ID/g at 4 h, and 0.28 ± 0.04% ID/g at 24 h). The uptake of radioactivity by the other organs varied from 0.09 ± 0.01% ID/g (heart) to 0.22 ± 0.01% ID/g (stomach) at 1 h, 0.05 ± 0.01% ID/g (intestines) to 0.16 ± 0.01% ID/g (lungs) at 4 h, and 0.02 ± 0.00% ID/g (blood) to 0.07 ± 0.01% ID/g (stomach and brain) at 24 h.
Although 99mTc-MDP was used for a study, the biodistribution of this radiotracer in mice was not reported (13).
In another study, the bone/blood (B/B) and bone/muscle (B/M) uptake ratios of 99mTc-CDTMP and 99mTc-MDP were determined for the animals (13). The B/B and B/M ratios for 99mTc-CDTMP were reported to be 40.4 and 54.9, respectively, and these ratios were higher than those for 99mTc-MDP (the actual B/B and B/M ratios for 99mTc-MDP were not reported).
Other Non-Primate Mammals
Scintigraphic studies were performed on rabbits injected with 99mTc-CDTMP (imaging was performed at 1 h after treatment); rabbits were also injected with 99mTc-MDP (imaging was performed at 3 h after treatment) for comparison purposes (13). Compared with 99mTc-MDP, the bone uptake of 99mTc-CDTMP was rapid; however, a high accumulation of radioactivity in the kidneys of animals treated with 99mTc-CDTMP was evident. The investigators suggested that this was probably because the labeled aminophosphonate compound had a high affinity for the kidney tissue. This also showed that 99mTc-CDTMP was excreted primarily through the urinary route. No blocking studies with unlabeled CDTMP were reported sine the bone is considered a high capacity target site.
No references are currently available.
Eleven cancer patients with bone metastases were intravenously injected with 99mTc-CDTMP, and scintigraphy was performed on the individuals 1 h later as described by Panwar et al. (13). Bone lesions were clearly visible in all the patients, and a semiquantitative region of interest analysis was performed to obtain the bone lesion/soft tissue (BL/ST) and bone lesion/normal bone (BL/NB) ratios. The BL/ST ratios for the patients varied from 5.6 ± 3.48 to 7.8 ± 1.10 with a mean of 6.8 ± 0.69. The BL/NB ratios varied from 5.36 ± 3.12 to 7.21 ± 0.68 with a mean of 5.67 ± 0.82.
From these studies the investigators concluded that 99mTc-CDTMP could be used to detect bone metastases in humans, and that CDTMP could perhaps be used to treat bone metastases after being labeled with a suitable high-energy nuclide (13).
No information is currently available.
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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.
Created: August 19, 2009; Last Update: October 15, 2009.
National Center for Biotechnology Information (US), Bethesda (MD)
Panwar P, Chuttani K, Mishra P, et al. 99mTc-Labeled trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid. 2009 Aug 19 [Updated 2009 Oct 15]. In: Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.