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99mTc-Labeled 1-hydroxy-2-(2-isopropyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic acid

, PhD
National Center for Biotechnology Information, NLM, Bethesda, MD 20894

Created: ; Last Update: November 1, 2011.

Chemical name:99mTc-Labeled 1-hydroxy-2-(2-isopropyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic acidimage 126920289 in the ncbi pubchem database
Abbreviated name:[99mTc]-iPIDP
Agent Category:Compound
Target:Bone (hydroxyapatite) at low concentration; farnesyl disphosphate (pyrophosphate) synthase (molecular target) at high concentration
Target Category:Other (Tissue); enzyme
Method of detection:Single-photon emission computed tomography (SPECT); gamma planar imaging
Source of signal / contrast:99mTc
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
Click on above structure of iPIDP for information in PubChem.



Bisphosphonates (BPs; also known as diphosphonates) labeled with technetium ([99mTc]-BPs) are often used in bone scintigraphy to detect osteoporosis and other skeletal-related events (SREs), including bone metastases (1). These chemicals are known to promote osteoclast apoptosis and have a strong affinity for hydroxyapatite, a component of the bone matrix. The mechanism of action of these bone-seeking compounds is described in detail elsewhere (2-4). Bone scintigraphy is usually performed 2–6 h after intravenous injection of a [99mTc]-BP, resulting in exposure of the patient to radiation for an extended time (due to slow clearance from circulation). To develop BPs that are more efficient and require only a short waiting time before bone scintigraphy, investigators generated various BPs, such as zoledronic acid (ZL), which contains an imidazole group in its structure, and evaluated their efficacy for the treatment of various bone-related diseases (5, 6). ZL was determined to be the most potent BP available for treating bone resorption and is approved by the United States Food and Drug Administration for the treatment of various tumor-induced SREs (7).

In an earlier study to further improve the potency of ZL, the imidazole group of the compound was modified to obtain 1-hydroxy-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)ethane-1,1-diyldiphosphonic acid (EMIDP), and the chemical was labeled with 99mTc to produce [99mTc]-EMIDP (1). The biodistribution of [99mTc]-EMIDP was investigated in normal mice, and the radiochemical was evaluated as a bone-imaging agent in rabbits. From these studies, the investigators concluded that [99mTc]-EMIDP bound selectively to the skeletal tissue in rabbits with superior selectivity compared to that of 99mTc-labeled methylene diphosphonate ([99mTc]-MDP), another BP that is commonly used in the clinic. In a effort to further explore the possibility of generating a high-potency ZL derivative similar to EMIDP, Lin et al. investigated optimization of the linker chain between the imidazolyl and the germinal BP group in the structure of ZL (8). For this, a ZL derivative, 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid was synthesized and labeled with 99mTc, and its biodistribution and bone-imaging properties (with single-photon emission computed tomography (SPECT) imaging) were investigated in normal mice and rabbits, respectively (8). As a continuation of this work, another ZL derivative with 2-isopropyl on the imidazole ring, 1-hydroxy-2-(2-isopropyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic acid (iPIDP), was prepared and labeled with 99mTc (to produce [99mTc]-iPIDP), and the biodistribution of the labeled compound was investigated in mice (9). In addition, the investigators used SPECT to study the bone-imaging characteristics of [99mTc]-iPIDP in rabbits.



The synthesis and 99mTc labeling of iPIDP has been described by Wang et al. (9). The radiochemical purity (RCP) of [99mTc]-iPIDP was reported to be >95%. The radiochemical yield (RCY) and specific activity of the labeled compound was not reported.

In one of the studies, 99mTc-labeled ZL ([99mTc]-ZL) was also used for comparison purposes, but the RCY, RCP, and specific activity of this labeled compound were not reported (9).

In Vitro Studies: Testing in Cells and Tissues


The in vitro stability of [99mTc]-iPIDP was investigated by incubating the radiolabeled compound for 6 h at room temperature in phosphate buffered saline (pH 4.0-6.0), and the RCP of the tracer was evaluated every 0.5 h with paper chromatography (9). At the end of the 6-h incubation, the RCP of [99mTc]-iPIDP was reported to be 96.6 ± 0.3%. This indicated that the tracer was stable at room temperature for at least 6 h.

Animal Studies



Wang et al. investigated the biodistribution of [99mTc]-iPIDP in Institute of Cancer Research mice (9). The animals (n = 5 mice/group) were injected with freshly prepared [99mTc]-iPIDP through the lateral tail vein, and the mice were euthanized at predetermined time points from 5 min to 240 min (4 h) postinjection (p.i.) to determine the amount of radioactivity accumulated in the major organs, including bone. Data from the study were presented as percent uptake of injected dose per gram tissue (% ID/g). The bone showed an accumulation of 3.96 ± 0.37% ID/g at 5 min p.i., which increased to 9.63 ± 0.64% ID/g at 60 min p.i. and decreased to 4.57 ± 0.14% ID/g at 240 min p.i. Among the other organs, the kidneys showed the highest uptake with 10.01 ± 0.68% ID/g at 5 min p.i., which decreased to 1.39 ± 0.01% ID/g at 240 min p.i. A similar trend in the uptake of radioactivity was observed in the other non-target organs. The bone/organ uptake ratios for muscle, spleen, brain, lung, heart, and liver were 12.19, 15.32, 95.55, 3.32, 8.78, and 11.22, respectively, at 15 min p.i. and increased to 67.83, 73.91, 429.06, 24.02, 66.00, and 37.45, respectively, at 60 min p.i. This indicated that accumulation of radioactivity in the soft tissue was low compared to the bone and that it was cleared rapidly from the soft tissues. No blocking studies were reported.

Other Non-Primate Mammals


For bone imaging, a New Zealand white rabbit (under anesthesia) was injected with [99mTc]-iPIDP through the marginal ear vein, and dynamic images of the animal were acquired every 5 min for the next 60 min. This was followed by the acquisition of static images every hour for 4 h (9). From the images it was clear that radioactivity in the animals was present selectively in the bones, and a low amount of the tracer was present in the various soft tissues, except in the kidneys and the bladder. These results were consistent with observations made during the biodistribution studies and showed that the radioactivity was cleared from circulation primarily through the urinary route.

For comparison with [99mTc]-iPIPD, dynamic bone images were also acquired from a New Zealand white rabbit injected with [99mTc]-ZL as described above (9). Images obtained with [99mTc]-ZL showed that both tracers had similar biodistribution patterns in the bones and the soft tissues. However, compared to [99mTc]-iPIPD, with [99mTc]-ZL there was a significantly higher (P value not reported) accumulation of radioactivity in the liver at the various time points.

Static images acquired from the animals with the two tracers showed that the rabbit skeleton was clearly visible with both [99mTc]-iPIPD and [99mTc]-ZL at 1 h p.i (9). A comparison of the images obtained with the two radiochemicals showed that with [99mTc]-iPIPDuptake of radioactivity by the liver was significantly lower than that with [99mTc]-ZL. Even at 4 h p.i., the liver was clearly visible with [99mTc]-ZL, indicating that the clearance of this tracer from the organ was more gradual than that of [99mTc]-iPIPD.

From these studies, the investigators concluded that [99mTc]-iPIPD was a promising agent for bone imaging in animals; however, further studies are necessary before it can be used in the clinic (9).

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.

Supplemental Information


No information is currently available.


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