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68Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[c(Arg-Gly-Asp-D-Tyr-Lys)]2

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

Created: ; Last Update: December 10, 2009.

Chemical name:68Ga-1,4,7-Triazacyclononane-1,4-7-triacetic acid-Glu-[c(Arg-Gly-Asp-D-Tyr-Lys)]2
Abbreviated name:68Ga-NOTA-RGD2, 68Ga-NOTA-E-[c(RGDfK)]2
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 (50% inhibition concentration (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 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). Li et al. (20) used 1,4,7-triazacyclononane-1,4-7-triacetic acid (NOTA) as a bifunctional chelator for labeling Glu-[cyclo(RGDyK)]2 (RGD2) to form (68Ga-NOTA-RGD2) for positron emission tomography (PET) imaging of αvβ3 receptors in nude mice bearing human glioblastoma U87MG tumors.



RGD2 was prepared with solid-phase peptide synthesis (20). Addition of the NOTA group to RGD2 was performed by mixing 2 µmol RGD2 with 6 μmol S-2-(4-isothiocyanatobenzyl)-NOTA in sodium bicarbonate buffer (pH 9) for 5 h at room temperature. NOTA-RGD2 was isolated with high-performance liquid chromatography (HPLC) with 52% yield. Molecular weight was determined with MALDI-TOF-MS to be m/z 1,800.2 Da (calculated molecular weight, 1,800.8 Da). For 68Ga labeling, a solution of 185 MBq (5 mCi) 68GaCl3 and 10 nmol RGD2 was heated for 10 min at 40°C. 68Ga-NOTA-RGD2 was purified with HPLC with a yield of 82% and a radiochemical purity of >98%. The specific activity was 9.7–13.6 MBq/nmol (0.26–0.37 mCi/nmol).

In Vitro Studies: Testing in Cells and Tissues


Li et al. (20) performed in vitro inhibition studies of NOTA-RGD2 in cultured human U87MG cells with 125I-echistatin. The 50% inhibition concentration (IC50) values were 189, 218, 60, and 16 nM for c(RGDyK), NOTA-RGD1, NOTA-RGD2, and NOTA-RGD4, respectively. NOTA-RGD1 and c(RGDyK) had comparable IC50 values, indicating that NOTA conjugation had little effect on the receptor binding affinity. Due to the dual-binding valency effect, NOTA-RGD2 and NOTA-RGD4 had two-fold and 12-fold higher binding affinity than NOTA-RGD1, respectively.

Animal Studies



Li et al. (20) performed ex vivo biodistribution studies of 3.7 MBq (100 μCi) 68Ga-NOTA-RGD2 in nude mice bearing U87MG xenografts at 1 h after injection. Tumor and kidney accumulation was 3.8 ± 0.7% and 4.3 ± 0.7% injected dose per gram (ID/g), whereas the accumulation values were ~1% ID/g or less in other tissues. The RGD2 dimer tracer exhibited a higher tumor accumulation than the RGD1 monomer tracer and lower background than the RGD4 tetramer tracer. Coinjection of excess c(RGDyK) (10 mg/kg) and 68Ga-NOTA-RGD2 inhibited the tumor accumulation by 95%, whereas the accumulation in the kidneys was inhibited by only 35%. Various small inhibitory effects were also observed in the other tissues and organs. PET imaging in nude mice bearing U87MG xenografts was performed with 3.7 MBq (0.1 mCi) 68Ga-NOTA-RGD2 for 2 h after injection. Quantitative analyses of PET imaging data showed that the radioactivity levels in the U87MG tumors (n = 3 mice) were 4.4% ID/g (5 min), 3.5% ID/g (15 min), 2.8% ID/g (30 min), 2.3% ID/g (60 min), and 1.9% ID/g (120 min). 68Ga-NOTA-RGD2 was excreted mainly through the kidneys. The tumor/muscle ratio was ~6 at 60 min after injection. Coinjection of c(RGDyK) and 68Ga-NOTA-RGD2 reduced the tumor accumulation to the background level at 60 min after injection. The radioactivity level in the liver, kidneys, and muscle was also reduced.

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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