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

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

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, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: February 16, 2012.

Chemical name:64Cu-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-cyclo(Arg-Gly-Asp-d-Phe-Lys)
Abbreviated name:64Cu-CB-TE2A-c(RGDfK)
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:64Cu
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about Integrin αv.



Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The αvβ3 integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the αvβ3 integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The αvβ3 antagonists are being studied as antitumor and antiangiogenic agents and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including αvβ3. Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10).

Most of the cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to αvβ3 (50% inhibition concentration (IC50), 7–40 nM) but not to αvβ5 (IC50, 600–4,000 nM) or αIIbβ3 (IC50, 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidomimetics have been found to have high accumulation in tumors in mice (12, 13). From these developments, [18F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of αvβ3 in cancer patients (14-18). Knetsch et al. (19) reported the development of 68Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys) (68Ga-NODAGA-c(RGDfK)) for positron emission tomography (PET) imaging of αvβ3 receptors in nude mice bearing melanoma tumors. 1-(1-Carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)3) was used to prepare 68Ga-NODAGA-c(RGDfK). Dumont et al. (20) chelated NODAGA-c(RGDfK) with 64Cu to form 64Cu-NODAGA-c(RGDfK) for PET imaging of αvβ3 receptors in nude mice bearing human glioblastoma tumors. For evaluation as a PET imaging agent for αvβ3, 64Cu has been attached to c(RGDfK) via bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) to form 64Cu-CB-TE2A-c(RGDfK). The CB-TE2A chelating agent is thought to be a more stable chelate for Cu.



Dumont et al. (20) prepared CB-TE2A-c(RGDfK) with CB-TE2A conjugation of the amino group of Lys. 64Cu-CB-TE2A-c(RGDfK) was prepared by reacting 3.3-6.6 nmol CB-TE2A-c(RGDfK) with 37–74 MBq (1–2 mCi) 64CuCl2 in ammonium acetate solution (pH 8) for 30 min at 95°C. 64Cu-CB-TE2A-c(RGDfK) was used without further purification, with a radiochemical purity of >97% as determined with high-performance liquid chromatography. The specific activity was 15–20 MBq/nmol (0.41–0.54 mCi/nmol). 64Cu-CB-TE2A-c(RGDfK) exhibited a partition coefficient (log D) of −2.92.

In Vitro Studies: Testing in Cells and Tissues


Dumont et al. (20) performed in vitro cell binding assays of 125I-echistatin with human glioblastoma U87MG cells (αvβ3 integrin-positive). natCu-CB-TE2A-c(RGDfK), natCu-NODAGA-c(RGDfK), and c(RGDyV) had IC50 values of 4.5 ± 0.5, 6.5 ± 0.2, and 4.3 ± 0.1 x 10-7 M, respectively.

Animal Studies



Dumont et al. (20) performed ex vivo biodistribution studies of 5 MBq (0.14 mCi) 64Cu-CB-TE2A-c(RGDfK) in nude mice (n = 4-7/group) bearing αvβ3-positive U87MG tumors. The accumulation in tumors was 3.66 ± 0.58% injected dose/gram (ID/g) and 2.99 ± 0.79% ID/g at 1 and 18 h after intravenous injection, respectively. The organ with the highest accumulation was the adrenal gland (2.63% ID/g), followed by the bone (2.57% ID/g), kidney (2.14% ID/g), liver (1.57% ID/g), stomach (1.52% ID/g), intestine (1.45% ID/g), spleen (1.33% ID/g) and lung (0.82% ID/g) at1 h after injection. The blood, pancreas, heart, and muscle had radioactivity values of <0.5% ID/g at 1 h. By 18 h after injection, the radioactivity levels in all organs studied declined to below that of the tumors. The tumor/muscle ratios were 13.61 and 30.75 at 1 and 18 h after injection, respectively. Coinjection of excess c(RGDfV) blocked the tumor accumulation by 90% at 1 h after injection (P < 0.01). Some inhibition was also observed in most normal organs studied.

PET imaging was performed in nude mice (n = 4) bearing U87MG tumors. Mice were injected with 5 MBq (0.14 mCi) 64Cu-CB-TE2A-c(RGDfK) and imaged at 1 and 18 h after injection (20). The tumors showed a good contrast at 1 h after injection. The liver, kidney, intestine, and urinary bladder were also visualized. At 18 h after injection, radioactivity levels in most organs were low, resulting a high tumor contrast (tumor/muscle ratio = 20.7). In comparison to 64Cu-NODAGA-c(RGDfK) (tumor/muscle ratio = 26.8), 64Cu-CB-TE2A-c(RGDfK) showed a lower tumor/muscle ratio.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


No publication is currently available.

Human Studies


No publication is currently available.


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