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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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64Cu-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Tyr-Lys)

64Cu-NODAGA-c(RGDyK)
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: June 6, 2013.

Chemical name:64Cu-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Tyr-Lys)
Abbreviated name:64Cu-NODAGA-c(RGDyK)
Synonym:
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:64Cu
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. 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 peptidomimetics have been found to have high accumulation in tumors in mice (12, 13). From these developments, [18F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for the imaging of αvβ3 in cancer patients (14-18). Knetsch et al. (19) reported the development of 68Ga-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys) (68Ga-NODAGA-c(RGDfK)) for positron emission tomography (PET) imaging of αvβ3 receptors in nude mice bearing melanoma tumors. 1-(1-Carboxy-3-carbo-tert-butoxypropyl)-4,7-(carbo-tert-butoxymethyl)-1,4,7-triazacyclononane (NODAGA(tBu)3) was used to prepare 68Ga-NODAGA-c(RGDfK). Dumont et al. (20) chelated NODAGA-c(RGDfK) with 64Cu to form 64Cu-NODAGA-c(RGDfK) for use with PET imaging of αvβ3 receptors in nude mice bearing human glioblastoma tumors. However, renal and liver excretion of 64Cu-NODAGA-c(RGDfK) was slow. Oxboel et al. (21) prepared 64Cu-NODAGA-c(Arg-Gly-Asp-d-Tyr-Lys) (64Cu-NODAGA-c(RGDyK)) to increase renal excretion of the tracer since d-Tyr is more hydrophilic than d-Phe.

Synthesis

[PubMed]

NODAGA-c(RGDyK) with NODAGA conjugation of the amino group of Lys (K) is commercially available. 64Cu-NODAGA-c(RGDyK) was prepared by reacting 2 nmol NODAGA-c(RGDyK) with 50–60 MBq (1.35–1.62 mCi) 64CuCl2 in ammonium acetate solution (pH 8.5) for 15 min at room temperature (21). 64Cu-NODAGA-c(RGDyK) was used without further purification and yielded a radiochemical purity of 93%–97% as determined with high-performance liquid chromatography. The specific activity was 25.3 MBq/nmol (0.68 mCi/nmol). 64Cu-NODAGA-c(RGDyK) remained >93% and 88% intact in the ammonium acetate buffer and mouse plasma after incubation for 24 h at room temperature, respectively. The hydrophilicity of 64Cu-NODAGA-c(RGDyK) was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Human lung bronchus carcinoid H727 tumors from nude mice exhibited high gene expression of human and mouse αv and VEGF-A as measured with quantitative real-time polymerase chain reaction (21). Expression of β3 was low for both species. No other in vitro studies (such as receptor binding, cellular accumulation) were performed with 64Cu-NODAGA-c(RGDyK).

Animal Studies

Rodents

[PubMed]

Oxboel et al. (21) performed ex vivo biodistribution studies of 2 MBq (0.05mCi) 64Cu-NODAGA-c(RGDyK) in nude mice (n = 5/group) bearing αvβ3-positive H272 tumors. The accumulation in tumors was 1.2 ± 0.2% injected dose/gram (ID/g), 0.7 ± 0.1% ID/g, and 0.6 ± 0.1% ID/g at 1, 2, and 18 h after intravenous injection, respectively. The organ with the highest accumulation at 1 h after injection was the kidney (2.2% ID/g), followed by the intestine (1.6% ID/g), liver (1.1% ID/g), and spleen (0.9% ID/g). The blood and muscle had radioactivity levels of <0.3% ID/g at 1 h. The washout from these normal tissues was rapid. The tumor/blood ratios were 12.7, 37.2, and 20.2 at 1, 2, and 18 h, respectively. The tumor/muscle ratios were 5.0, 7.3, and 7.1 at 1, 2, and 18 h after injection, respectively. There was significant correlation of tumor radioactivity at 2 h with mouse αv integrin (R = 0.75, P < 0.05), mouse VEGF-A (R = 0.81, P < 0.05), and human αv integrin (R = 0.86, P < 0.01). No blocking studies were performed.

PET imaging was performed in a nude mouse bearing H272 tumors injected with 1.6 MBq (0.04 mCi) 64Cu-NODAGA-c(RGDyK) and imaged at 1, 2, and 18 h after injection (21). The tumors showed good contrast at 1 h after injection. The tumor radioactivity accumulation was 1.15%, 0.99%, and 0.76% ID/g at 1, 2, and 18 h after injection, respectively. The tumor/muscle ratios were 6.9 ± 0.8 at these time points. No blocking studies were performed.

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

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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]
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Grzesik W.J. Integrins and bone--cell adhesion and beyond. Arch Immunol Ther Exp (Warsz) 1997;45(4):271–5. [PubMed: 9523000]
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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]
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Mousa S.A. alphav Vitronectin receptors in vascular-mediated disorders. Med Res Rev. 2003;23(2):190–9. [PubMed: 12500288]
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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.
Haubner R., Decristoforo C. Radiolabelled RGD peptides and peptidomimetics for tumour targeting. Front Biosci. 2009;14:872–86. [PubMed: 19273105]
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Schottelius M., Laufer B., Kessler H., Wester H.J. Ligands for mapping alphavbeta3-integrin expression in vivo. Acc Chem Res. 2009;42(7):969–80. [PubMed: 19489579]
14.
Beer A.J., Grosu A.L., Carlsen J., Kolk A., Sarbia M., Stangier I., Watzlowik P., Wester H.J., Haubner R., Schwaiger M. [18F]galacto-RGD positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13(22 Pt 1):6610–6. [PubMed: 18006761]
15.
Beer A.J., Haubner R., Goebel M., Luderschmidt S., Spilker M.E., Wester H.J., Weber W.A., Schwaiger M. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med. 2005;46(8):1333–41. [PubMed: 16085591]
16.
Beer A.J., Haubner R., Sarbia M., Goebel M., Luderschmidt S., Grosu A.L., Schnell O., Niemeyer M., Kessler H., Wester H.J., Weber W.A., Schwaiger M. Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res. 2006;12(13):3942–9. [PubMed: 16818691]
17.
Beer A.J., Lorenzen S., Metz S., Herrmann K., Watzlowik P., Wester H.J., Peschel C., Lordick F., Schwaiger M. Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG. J Nucl Med. 2008;49(1):22–9. [PubMed: 18077538]
18.
Beer A.J., Niemeyer M., Carlsen J., Sarbia M., Nahrig J., Watzlowik P., Wester H.J., Harbeck N., Schwaiger M. Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18F-Galacto-RGD PET. J Nucl Med. 2008;49(2):255–9. [PubMed: 18199623]
19.
Knetsch P.A., Petrik M., Griessinger C.M., Rangger C., Fani M., Kesenheimer C., von Guggenberg E., Pichler B.J., Virgolini I., Decristoforo C., Haubner R. [(68)Ga]NODAGA-RGD for imaging alpha(v)beta (3) integrin expression. Eur J Nucl Med Mol Imaging. 2011;38(7):1303–12. [PubMed: 21487838]
20.
Dumont R.A., Deininger F., Haubner R., Maecke H.R., Weber W.A., Fani M. Novel (64)Cu- and (68)Ga-labeled RGD conjugates show improved PET imaging of alpha(nu)beta(3) integrin expression and facile radiosynthesis. J Nucl Med. 2011;52(8):1276–84. [PubMed: 21764795]
21.
Oxboel J., Schjoeth-Eskesen C., El-Ali H.H., Madsen J., Kjaer A. (64)Cu-NODAGA-c(RGDyK) Is a Promising New Angiogenesis PET Tracer: Correlation between Tumor Uptake and Integrin alpha(V)beta(3) Expression in Human Neuroendocrine Tumor Xenografts. Int J Mol Imaging. 2012;2012:379807. [PMC free article: PMC3469102] [PubMed: 23091717]

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