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68Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Lys)

, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: May 12, 2011.

Chemical name:68Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Lys)image 117703374 in the ncbi pubchem database
Abbreviated name:68Ga-DOTA-E-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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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. Antagonists of αvβ3 are being studied as antitumor and antiangiogenic agents, and the agonists of αvβ3 are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of 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 cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to αvβ3 (inhibition concentration (IC50), 7–40 nM) but not to integrins αvβ5 (IC50, 600–4,000 nM) or αIIbβ3 (IC50, 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of 111In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Lys) (111In-DOTA-E-c(RGDfK)) for single-photon emission computed tomography imaging αvβ3 receptors in nude mice bearing ovarian carcinoma tumors. In this chapter, Dijkgraaf et al. (14) also reported the evaluation of 68Ga-DOTA-E-c(RGDfK) for positron emission tomography (PET) imaging αvβ3 receptors in tumor, which is the topic of this chapter.



Dijkgraaf et al. (14) prepared the synthesis of 68Ga-DOTA-E-c(RGDfK) by reacting DOTA-E-c(RGDfK) with 68Ga in ammonium acetate buffer (pH ~5.5) at 95°C for 20 min. Radiochemical purity was ~97% as determined by high-performance liquid chromatography. The maximum specific activity was 11.2 MBq/nmol (0.3 mCi/nmol). 68Ga-DOTA-E-c(RGDfK) was stable in phosphate-buffered saline and human serum at 37°C for 2 h.

In Vitro Studies: Testing in Cells and Tissues


Dijkgraaf et al. (14) performed in vitro solid-phase binding assays of 111In-DOTA-E-[c(RGDfK)]2 with human αvβ3 integrin. natGa-DOTA-E-c(RGDfK) (monomer) had an IC50 value of 23.9 ± 1.22 nM. natGa-DOTA-E-[c(RGDfK)]2 (dimer) had an IC50 value of 8.99 ± 1.20 nM. natGa-DOTA-E-{E-[c(RGDfK)]2}2 (tetramer) had an IC50 value of 1.74 ± 1.18 nM.

Animal Studies



Dijkgraaf et al. (14) performed ex vivo biodistribution studies of 68Ga-DOTA-E-c(RGDfK) in nude mice (n = 3/group) bearing SK-RC-52 human renal carcinoma tumors at 2 h after injection. The tumor accumulation was 3.3 ± 0.3% injected dose/gram (ID/g). The organ with the highest accumulation was the intestine (~4% ID/g), followed by the spleen (~2.5% ID/g), kidney (~2.5% ID/g), liver (~2.0% ID/g) and colon (~2.0% ID/g). Coinjection of 100-fold excess DOTA-E-[c(RGDfK)]2 resulted in >90% reduction of radioactivity in the tumor. The accumulation was also markedly reduced in the liver, lung, intestine, colon and spleen (this may be partly mediated by αvβ3 integrin in these tissues) but not in the kidney. PET scan showed that the tumor was clearly visualized at 2 h after injection of 10 MBq (0.27 mCi) 68Ga-DOTA-E-c(RGDfK).

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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