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68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(Arg-Gly-Asp-D-Phe-Lys)

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

Created: ; Last Update: December 10, 2009.

Chemical name:68Ga-1,4,7,10-Tetraazacyclododecane- N,N',N'',N'''-tetraacetic acid-cyclo(Arg-Gly-Asp-D-Phe-Lys)
Abbreviated name:68Ga-DOTA-c(RGDfK)
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:68Ga
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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 peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [18F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of αvβ3 in cancer patients (14-19). Decristoforo et al. (20) reported the development of 68Ga-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(Arg-Gly-Asp-D-Phe-Lys) (68Ga-DOTA-c(RGDfK)) for positron emission tomography (PET) imaging of αvβ3 receptors in nude mice bearing melanoma tumors.



Decristoforo et al. (20) prepared DOTA-c(RGDfK) with DOTA conjugation of the amino group of Lys. 68Ga-DOTA-c(RGDfK) was prepared by reacting 20–40 µg DOTA-c(RGDfK) with 250–500 MBq (6.76–13.51 mCi) 68GaCl3 in sodium acetate solution for 7 min at 80°C. 68Ga-DOTA-c(RGDfK) was purified with column chromatography, with a radiochemical purity of >95% as determined with high-performance liquid chromatography. 68Ga-DOTA-c(RGDfK) was stable in human serum with >95% intact after 120 min of incubation.

In Vitro Studies: Testing in Cells and Tissues


Decristoforo et al. (20) performed in vitro solid-phase binding assays of 125I-echistatin with human αvβ3 integrin. DOTA-c(RGDfK) and DOTA-RGD had IC50 values of 3.7 ± 0.5 and 5.5 ± 1.6 nM, respectively. The internalization of 68Ga-DOTA-c(RGDfK) (10 nM) into M21 (αvβ3-positive) melanoma cells in culture was blocked by 10 µM c(RGDyV).

Animal Studies



Decristoforo et al. (20) performed biodistribution studies of 68Ga-DOTA-c(RGDfK) in nude mice bearing M21 tumors. The tumor accumulation was 2.8% ID/g at 1 h after injection. The kidneys, liver, lung, stomach, intestine, and spleen had high levels of radioactivity (1.5–2.5% ID/g) at 1 h after injection. The accumulation of 68Ga-DOTA-c(RGDfK) in M21-L (αvβ3-negative) melanoma tumors was low (0.7% ID/g). PET imaging was performed in nude mice bearing M21 and M21-L tumors in the right and left flank, respectively. Mice were injected with 37 MBq (1 mCi) 68Ga-DOTA-c(RGDfK) and imaged for 90 min. The M21 tumors but not the M21-L tumors were clearly visualized. Blood radioactivity curve showed a bi-exponential blood clearance with t1 and t2 values of 140 s and 40 min, respectively. No blocking experiment was performed, although the use of tumors that are αvβ3-positive or αvβ3-negative is consistent with specific binding.

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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