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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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[99mTc-Gly-Gly-Cys]-Ornithine-ornithine-ornithine-cyclo(Arg-Gly-Asp-d-Phe-Lys)

[99mTc-GGC]-(Orn)3-c(RGDfK)
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: April 18, 2013.

Chemical name:[99mTc-Gly-Gly-Cys]-Ornithine-ornithine-ornithine-cyclo(Arg-Gly-Asp-d-Phe-Lys)
Abbreviated name:[99mTc-GGC]-(Orn)3-c(RGDfK)
Synonym:
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar imaging
Source of signal:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about integrin αv.

Background

[PubMed]

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 RGD analogs 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 (SPECT) imaging αvβ3 receptors in nude mice bearing ovarian carcinoma tumors. Tsiapa et al. (14) prepared [99mTc -Gly-Gly-Cys]-ornithine-ornithine-ornithine-cyclo(Arg-Gly-Asp-d-Phe-Lys) ([99mTc-GGC]-(Orn)3-c(RGDfK)) as a radioligand for use in tumor imaging showing relatively high tumor accumulation and renal elimination with low abdominal accumulation in mice.

Related Resource Links:

Synthesis

[PubMed]

Tsiapa et al. (14) prepared the synthesis of [99mTc-GGC]-(Orn)3-c(RGDfK) by reacting GGC-(Orn)3-c(RGDfK) with 370–555 MBq (10–15 mCi) Na99mTcO4, sodium gluconate, sodium bicarbonate, and stannous chloride for 30 min at 37°C. [99mTc-GGC]-(Orn)3-c(RGDfK) was purified with high-performance liquid chromatography. The radiochemical yield was >95%. The specific activity of [99mTc-GGC]-(Orn)3-c(RGDfK) was not reported. [99mTc-GGC]-(Orn)3-c(RGDfK) exhibited a log P7.4 value of −2.45 ± 0.01 (n = 3).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

[99mTc-GGC]-(Orn)3-c(RGDfK) remained 92.7% and 93.3% intact in the presence of 0.1 µM Cys for 60 min and 120 min (14), respectively, at 37ºC. [99mTc-GGC]-(Orn)3-c(RGDfK) remained >90% intact in human plasma for 120 min at 37ºC.

Animal Studies

Rodents

[PubMed]

Tsiapa et al. (14) performed ex vivo biodistribution studies of 3.7 MBq (0.1 mCi) [99mTc-GGC]-(Orn)3-c(RGDfK) at 5, 30, 60, and 120 min in nude mice (n = 3–5/group) bearing U87MG human glioblastoma tumors. The initial radioactivity accumulation in the U87MG tumors expressing the αvβ3 integrin was 4.00 ± 0.05% injected dose (ID)/g at 5 min and decreased to 3.87 ± 0.48% ID/g at 60 min and 3.39 ± 1.05% ID/g at 120 min. At 60 min, the highest radioactive concentration was found in the kidney (72.17% ID/g), followed by the lung (2.27% ID/g), intestines (1.98% ID/g), liver (1.60% ID/g), and stomach (1.19% ID/g). Blood levels were 0.91% ID/g at 30 min and 0.88% ID/g at 60 min. Co-injection with excess c(RGDfK) (0.1 mg/mouse) reduced radioactivity accumulation by 70% in the tumors at 60 min. Maximum tumor/blood and tumor/muscle ratios were 4.39 at 60 min and 10.08 at 120 min, respectively.

Dynamic SPECT gamma planar imaging was performed in nude mice (n = 4) bearing U87MG tumors for 90 min after injection of 3.7 MBq (0.1 mCi) [99mTc-GGC]-(Orn)3-c(RGDfK) (14). The tumors were clearly visualized as early as 5 min and at the end of 90 min scan with 6%–7% ID. The kidneys and urinary bladder exhibited 30%–40% ID and 25% ID during the 90-min scans. In one mouse with co-injection with excess c(RGDfK) the tumor was not visualized.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Hynes R.O. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69(1):11–25. [PubMed: 1555235]
2.
Jin H., Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer. 2004;90(3):561–5. [PMC free article: PMC2410157] [PubMed: 14760364]
3.
Varner J.A., Cheresh D.A. Tumor angiogenesis and the role of vascular cell integrin alphavbeta3. Important Adv Oncol. 1996:69–87. [PubMed: 8791129]
4.
Wilder R.L. Integrin alpha V beta 3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Ann Rheum Dis. 2002;61 Suppl 2:ii96–9. [PMC free article: PMC1766704] [PubMed: 12379637]
5.
Grzesik W.J. Integrins and bone--cell adhesion and beyond. Arch Immunol Ther Exp (Warsz) 1997;45(4):271–5. [PubMed: 9523000]
6.
Kumar C.C. Integrin alpha v beta 3 as a therapeutic target for blocking tumor-induced angiogenesis. Curr Drug Targets. 2003;4(2):123–31. [PubMed: 12558065]
7.
Ruegg C., Dormond O., Foletti A. Suppression of tumor angiogenesis through the inhibition of integrin function and signaling in endothelial cells: which side to target? Endothelium. 2002;9(3):151–60. [PubMed: 12380640]
8.
Kerr J.S., Mousa S.A., Slee A.M. Alpha(v)beta(3) integrin in angiogenesis and restenosis. Drug News Perspect. 2001;14(3):143–50. [PubMed: 12819820]
9.
Mousa S.A. alphav Vitronectin receptors in vascular-mediated disorders. Med Res Rev. 2003;23(2):190–9. [PubMed: 12500288]
10.
Haubner R., Wester H.J. Radiolabeled tracers for imaging of tumor angiogenesis and evaluation of anti-angiogenic therapies. Curr Pharm Des. 2004;10(13):1439–55. [PubMed: 15134568]
11.
Haubner R., Wester H.J., Burkhart F., Senekowitsch-Schmidtke R., Weber W., Goodman S.L., Kessler H., Schwaiger M. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med. 2001;42(2):326–36. [PubMed: 11216533]
12.
Chen X., Park R., Shahinian A.H., Tohme M., Khankaldyyan V., Bozorgzadeh M.H., Bading J.R., Moats R., Laug W.E., Conti P.S. 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. Nucl Med Biol. 2004;31(2):179–89. [PubMed: 15013483]
13.
Dijkgraaf I., Kruijtzer J.A., Frielink C., Corstens F.H., Oyen W.J., Liskamp R.M., Boerman O.C. Alpha v beta 3 integrin-targeting of intraperitoneally growing tumors with a radiolabeled RGD peptide. Int J Cancer. 2007;120(3):605–10. [PubMed: 17096340]
14.
Tsiapa I., Loudos G., Varvarigou A., Fragogeorgi E., Psimadas D., Tsotakos T., Xanthopoulos S., Mihailidis D., Bouziotis P., Nikiforidis G.C., Kagadis G.C. Biological evaluation of an ornithine-modified (99m)Tc-labeled RGD peptide as an angiogenesis imaging agent. Nucl Med Biol. 2013;40(2):262–72. [PubMed: 23238128]

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