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68Ga-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys)

68Ga-NODAGA-c(RGDfK)
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: November 10, 2011.

Chemical name:68Ga-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-cyclo(Arg-Gly-Asp-d-Phe-Lys)
Abbreviated name:68Ga-NODAGA-c(RGDfK), 68Ga-NODAGA-RGD
Synonym:
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:68Ga
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 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).

Synthesis

[PubMed]

Knetsch et al. (19) prepared NODAGA-c(RGDfK) with NODAGA conjugation of the amino group of Lys. 68Ga-NODAGA-c(RGDfK) was prepared by reacting ~11 nmol NODAGA-c(RGDfK) with 100–200 MBq (2.7–5.4 mCi) 68GaCl3 in sodium acetate solution (pH 5) for 15 min at room temperature. 68Ga-NODAGA-c(RGDfK) was used without further purification, with a radiochemical purity of >96% as determined with high-performance liquid chromatography. 68Ga-NODAGA-c(RGDfK) was stable in human serum with >95% intact after 90 min of incubation. The specific activity was 10–20 MBq/nmol (0.27–0.54 mCi/nmol). 68Ga-NODAGA-c(RGDfK) exhibited a partition coefficient (log D) of −3.6.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Knetsch et al. (19) performed in vitro solid-phase binding assays of 125I-echistatin with human αvβ3 integrin. NODAGA-c(RGDfK) and c(RGDyV) had IC50 values of 4.7 ± 1.6 and 2.8 ± 1.0 nM, respectively. The internalization of 68Ga-NODAGA-c(RGDfK) (10 nM) into αvβ3-positive M21 melanoma cells in culture was blocked by 10 µM c(RGDyV).

Animal Studies

Rodents

[PubMed]

Knetsch et al. (19) performed ex vivo biodistribution studies of 1 MBq (0.027 mCi) 68Ga-NODAGA-c(RGDfK) in nude mice (n = 10) bearing an αvβ3-positive M21 tumor on the right flank and an αvβ3-negative M21-L tumor on the left flank. The accumulation in the M21 and M21-L tumors was 1.3% ID/g and 0.3% ID/g at 1 h after injection, respectively. The kidneys, liver, lung, stomach, intestine, and spleen had moderate levels of radioactivity (0.7–1.7% ID/g) at 1 h after injection. The blood, pancreas, heart, and muscle had radioactivity values less than that of the M21-L tumor. No blocking studies were reported so selectivity is derived from the % ID/g in αvβ3 positive and negative tumors. Accumulation in both tumors is low.

PET imaging was performed in nude mice (n = 4) bearing M21 and M21-L tumors in the right and left flank, respectively. Mice were injected with 10 MBq (0.27 mCi) 68Ga-NODAGA-c(RGDfK) and imaged for 90 min. The M21 tumors were clearly visualized, but the M21-L tumors were not. The M21/muscle, M21/M21-L, M21/heart, M21/liver, and M21/kidney ratios were 4.0, 2.6, 2.7, 1.2, and 1.0 at 90 min after injection, respectively. In comparison, the M21/muscle ratio was 2.5 for 68Ga-DOTA-c(RGDfK). No blocking experiment was performed, although the use of tumors that are αvβ3-positive or αvβ3-negative is consistent with specific binding.

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]
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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]
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.
Haubner R., Decristoforo C. Radiolabelled RGD peptides and peptidomimetics for tumour targeting. Front Biosci. 2009;14:872–86. [PubMed: 19273105]
13.
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]

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