NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

Cover of Molecular Imaging and Contrast Agent Database (MICAD)

Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

Show details

68Ga-Labeled (4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD)

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

Created: ; Last Update: November 21, 2012.

Chemical name:68Ga-Labeled (4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD)image 152188297 in the ncbi pubchem database
Abbreviated name:[68Ga]BPAMD
Agent Category:Compound
Target:Hydroxyapatite; farnesyl diphosphate synthase
Target Category:Others (bone); enzyme
Method of detection:Positron emission tomography (PET)
Source of signal / contrast:68Ga
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
Click on structure of [68Ga]BPAMD for more information in PubChem.



Bisphosphonates (BPs; also known as diphosphonates), such as methylene diphosphonate (MDP) and zoledronic acid, can be labeled with technetium-99m ([99mTc]-BPs) for bone scintigraphy (gamma planar imaging or single-photon emission computed tomography (SPECT)) 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 exact mechanism of action of these bone-seeking compounds is described in detail elsewhere (2-4). Although the 99mTc-labeled compounds have high sensitivity, selectivity, and accuracy for the detection of SREs, they are known to generate some false positive and false negative results in the clinic (5). [18F]-Fluoride is another nuclide that is commonly used for bone imaging with positron emission tomography (PET) and is believed to be superior to [99mTc]-BPs for the diagnosis of SREs (6). However, the main limitations of using 18F are the requirement of a cyclotron to produce it and the high costs that are associated with the production of this radionuclide (5). In an effort to develop an imaging compound that does not have the limitations of tracers that are currently used to detect SREs with scintigraphy or PET, a bisphosphonate labeled with 68Ga was developed and shown to be potentially useful for imaging the mouse skeletal system with PET (5).

The main advantage of using 68Ga (half-life = 68 min; β+ = 89%; E+βmax = 1.9 MeV) for bone imaging over either 99mTc (half-life = 6 h; γ+ = 100%; E+γmax = 140 keV) or 18F (half-life = ~110 min; β+ = 97%; E+βmax = 0.635 MeV) as a radiolabel is that 68Ga can be produced economically on-site with a 68Ge/68Ga generator (5, 7). In addition, images obtained with PET have a higher spatial resolution compared with those obtained with SPECT (7). In an ongoing effort to develop a compound that could be used for the targeted imaging of bone metastases, a novel 1,4,7,10-tetraazacyclododecane-N,N',N,N'-tetraacetic acid (DOTA) derivative that contained a bisphosphonate within its structure ((4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD)) was developed (8, 9), labeled with 68Ga ([68Ga]BPAMD), and shown to be suitable for the imaging of bone metastases in mice (7) and humans (10).



The synthesis of BPAMD is described elsewhere (8, 9). The labeling of BPAMD with 68Ga was initially optimized for the concentration of the ligand (BPAMD), pH, time, and temperature as detailed by Fellner et al. (7). The radiochemical yield of the labeling reaction was reported to be 90%, and the radiochemical purity of the final product after purification was >98% as determined with high-performance liquid chromatography. The specific activity of [68Ga]BPAMD was not reported.

In Vitro Studies: Testing in Cells and Tissues


The in vitro binding characteristics of [68Ga]BPAMD were studied by exposing the radiochemical to commercially available synthetic hydroxyapatite (Hap) (7). The binding of [68Ga]BPAMD to the matrix was reported as the percent of 68Ga absorbed to Hap and determined to be 81.5 ± 0.5% within 10 min at ambient temperature.

The stability of [68Ga]BPAMD was investigated (n = 5 studies) by incubating the probe in the presence or absence of apo-transferrin (39.2 nmol/mL) in phosphate-buffered saline (PBS; pH 7.4) for 3 h at 37°C (7). Thin-layer chromatographic analysis showed that 4.2 ± 0.8% of 68Ga had transchelated by the end of the incubation when it was incubated with PBS alone, whereas 9.1 ± 0.6% of 68Ga had transchelated in the presence of apo-transferrin during the same time period.

Animal Studies



The biodistribution of [68Ga]BPAMD was studied in a healthy rat by administering 15 MBq (555 μCi) of the radiochemical through the tail vein of the animals (7). Dynamic PET scans of the rodent were acquired for 60 min postinjection (p.i.) From the images it was apparent that maximum radioactivity was present in the shoulder joints and certain areas of the vertebral column of the animal that show a relatively high remodeling activity. In the backbone, the accumulation of label in the humerus, sternum, and scapula was 2.49-fold, 2.88-fold, and 2.08-fold higher, respectively, compared with the solid bone. This indicated that the tracer accumulated preferentially in those areas of the skeleton that exhibited a high metabolic activity in the animals. No blocking studies were reported.

In another study, rats were injected with Walker 256 cells to induce bone metastases in the rodents (7). Two weeks later, the animals (n = 7 rats) were injected with 20.5 ± 0.5 MBq (758.5 ± 18.5 μCi) [68Ga]BPAMD to evaluate the use of this tracer for the visualization of metastatic lesions in the skeletal system of the rats. Whole-body PET scans acquired from the animals at 60–70 min p.i. showed that only five animals had developed metastasis in the tibia. The lesions were reported to accumulate 3.97 ± 1.82-fold higher radioactivity (n = 4 rats) compared with a healthy area of the bone that served as an intraindividual control. Presence of osteolytic metastasis in the tibia of the animals was confirmed with histological examination of the tissue.

From these studies, the investigators concluded that [68Ga]BPAMD can be used for the detection of bone metastases in rodents (7).

Other Non-Primate Mammals


No reference is currently available.

Non-Human Primates


No reference is currently available.

Human Studies


A patient known to have extensive bone metastasis of prostate cancer was intravenously injected with 462 MBq (~17 mCi) [68Ga]BPAMD (10). Whole-body PET images of the individual revealed that the radioactivity had accumulated in multiple lesions of the vertebrae, ribs, and the proximal extremities of the patient. For comparison, PET images were also acquired from the patient after injection of 270 MBq (~10 mCi) [18F]-fluoride, and the images showed that the metastatic lesions were present in the entire skeletal system of the patient as observed with [68Ga]BPAMD. With [68Ga]BPAMD, the maximal standardized uptake values (SUVmax) of the tenth and twelfth vertebrae were 77.1 and 62.1, respectively, compared with the SUVmax values of 39.1 and 39.2, respectively, obtained with 18F. This indicated that [68Ga]BPAMD was probably superior to 18F for the visualization of bone metastasis in humans (10).

Supplemental Information


No information is currently available.


Lin J., Luo S., Chen C., Qiu L., Wang Y., Cheng W., Ye W., Xia Y. Preparation and preclinical pharmacological study on a novel bone imaging agent (99m)Tc-EMIDP. Appl Radiat Isot. 2010;68(9):1616–22. [PubMed: 20363146]
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]
Zhang Y., Cao R., Yin F., Hudock M.P., Guo R.T., Krysiak K., Mukherjee S., Gao Y.G., Robinson H., Song Y., No J.H., Bergan K., Leon A., Cass L., Goddard A., Chang T.K., Lin F.Y., Van Beek E., Papapoulos S., Wang A.H., Kubo T., Ochi M., Mukkamala D., Oldfield E. Lipophilic bisphosphonates as dual farnesyl/geranylgeranyl diphosphate synthase inhibitors: an X-ray and NMR investigation. J Am Chem Soc. 2009;131(14):5153–62. [PMC free article: PMC2753403] [PubMed: 19309137]
Mitterhauser M., Toegel S. Radiopharmaceutical considerations on bone seeker uptake: should we learn from therapeutical targets of bisphosphonates? Nucl Med Biol. 2011;38(5):617–8. [PubMed: 21718935]
Suzuki K., Satake M., Suwada J., Oshikiri S., Ashino H., Dozono H., Hino A., Kasahara H., Minamizawa T. Synthesis and evaluation of a novel 68Ga-chelate-conjugated bisphosphonate as a bone-seeking agent for PET imaging. Nucl Med Biol. 2011;38(7):1011–8. [PubMed: 21982572]
Kruger S., Buck A.K., Mottaghy F.M., Hasenkamp E., Pauls S., Schumann C., Wibmer T., Merk T., Hombach V., Reske S.N. Detection of bone metastases in patients with lung cancer: 99mTc-MDP planar bone scintigraphy, 18F-fluoride PET or 18F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2009;36(11):1807–12. [PubMed: 19504092]
Fellner M., Biesalski B., Bausbacher N., Kubicek V., Hermann P., Rosch F., Thews O. (68)Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter. Nucl Med Biol. 2012;39(7):993–9. [PubMed: 22633217]
Kubicek V., Rudovsky J., Kotek J., Hermann P., Vander Elst L., Muller R.N., Kolar Z.I., Wolterbeek H.T., Peters J.A., Lukes I. A bisphosphonate monoamide analogue of DOTA: a potential agent for bone targeting. J Am Chem Soc. 2005;127(47):16477–85. [PubMed: 16305234]
Vitha T., Kubicek V., Hermann P., Elst L.V., Muller R.N., Kolar Z.I., Wolterbeek H.T., Breeman W.A., Lukes I., Peters J.A. Lanthanide(III) complexes of bis(phosphonate) monoamide analogues of DOTA: bone-seeking agents for imaging and therapy. J Med Chem. 2008;51(3):677–83. [PubMed: 18181563]
Fellner M., Baum R.P., Kubicek V., Hermann P., Lukes I., Prasad V., Rosch F. PET/CT imaging of osteoblastic bone metastases with (68)Ga-bisphosphonates: first human study. Eur J Nucl Med Mol Imaging. 2010;37(4):834. [PubMed: 20069291]
PubReader format: click here to try


  • PubReader
  • Print View
  • Cite this Page
  • PDF version of this page (812K)
  • MICAD Summary (CSV file)

Search MICAD

Limit my Search:

Related information

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...