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68Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-isothiocyanatobenzyl-c(Arg-Gly-Asp-d-Tyr-Lys)

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

Created: ; Last Update: April 7, 2011.

Chemical name:68Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-isothiocyanatobenzyl-c(Arg-Gly-Asp-d-Tyr-Lys)
Abbreviated name:68Ga-NOTA-RGD, 68Ga-NOTA-SCN-Bz-c(RGDyK)
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal\contrast:68Ga
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about integrin αvβ3.



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. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to αvβ3 (IC50, 7–40 nM) but not to αvβ5 (IC50, 600–4,000 nM) or αIIbβ3 (IC50, 700–5,000 nM) integrins. Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Jeong et al. (13) used 2-(p-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4-7-triacetic acid (SCN-Bz-NOTA) as a bifunctional chelator for labeling c(RGDyK) to form 68Ga-1,4,7-triazacyclononane-1,4-7-triacetic acid-isothiocyanatobenzyl-c(Arg-Gly-Asp-d-Tyr-Lys) (68Ga-NOTA-RGD) for positron emission tomography (PET) imaging of αvβ3 receptors in nude mice bearing tumor xenografts.



Addition of a NOTA group to RGD was performed by mixing 0.60 µmol RGD with 0.66 umol SCN-Bz-NOTA in sodium carbonate buffer (pH 9.5) for 20 h at room temperature (13). SCN-Bz-NOTA-RGD was isolated with high-performance liquid chromatography (HPLC). MALDI-TOF-MS was m/z 1,071 (calculated molecular weight, 1,069.5). For 68Ga labeling, a solution of 740 MBq (20 mCi) 68GaCl3 and 30 nmol RGD was heated for 10 min at room temperature. 68Ga-NOTA-RGD was purified with HPLC, with a yield of 89% and a radiochemical purity of >98%. The specific activity was 17.4 GBq/µmol (0.47 Ci/µmol) at the end of purification. 68Ga-NOTA-RGD was stable for >4 h at room temperature.

In Vitro Studies: Testing in Cells and Tissues


Jeong et al. (13) performed in vitro inhibition studies of NOTA-RGDand human αvβ3 integrin with 125I-c(RGDyK). The inhibition constant values were 1.3 nM and 1.9 nM for c(RGDyK) and NOTA-RGD, respectively.

Animal Studies



Jeong et al. (13) performed ex vivo biodistribution studies of 5.6 MBq (0.15 mCi) 68Ga-NOTA-RGD in nude micebearing human colon cancer SNU-C4 xenografts at 1 h and 2 h after injection. Tumor and kidney accumulation values were 5.1 ± 1.0% and 5.3 ± 1.3% injected dose per gram (ID/g) at 1 h after injection, respectively. Lower levels were observed in the liver, intestines, lung, spleen, and heart (<2.2% ID/g). The tumor/blood and tumor/muscle ratios at 1 h after injection were 10.3 ± 4.8 and 9.3 ± 3.9, respectively. PET imaging in the tumor-bearing micewas performed with 16 MBq (0.43 mCi) 68Ga-NOTA-RGD at 1 h and 2 h after injection. The tumors were clearly visualized at these two time points. High levels of radioactivity were found in the kidneys and urinary bladder, with less accumulation in the liver and intestine. Co-injection of excess c(RGDyK) reduced the tumor accumulation to the background level at 1 h after injection. The radioactivity levels in the liver and kidneys were also reduced. In another experiment, 68Ga-NOTA-RGD accumulation in ischemic hind limb muscle (1.6 ± 0.2% ID/g) was reduced significantly with c(RGDyK) to near the level in normal hind limb (0.5 ± 0.1% ID/g, P < 0.01).

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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