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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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Al18F-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-Phe-Lys)]2

Al18F-NODAGA-E-[c(RGDfK)]2
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: June 13, 2013.

Chemical name:Al18F-1,4,7-Triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-Phe-Lys)]2
Abbreviated name:Al18F-NODAGA-E-[c(RGDfK)]2
Synonym:
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:18F
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). Extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) contain a tripeptide sequence consisting of Arg-Gly-Asp (RGD), which binds to a variety of integrins, including αvβ3. Various radiolabeled antagonists have been introduced for use with the 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 (c(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 c(RGD) peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the evaluation of Al18F-1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid-Glu-[cyclo(Arg-Gly-Asp-d-Phe-Lys)]2 (Al18F-NODAGA-E-[c(RGDfK)]2) for use with positron emission tomography (PET) imaging of αvβ3 in tumors.

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Synthesis

[PubMed]

Dijkgraaf et al. (13) prepared the synthesis of Al18F-NODAGA-E-[c(RGDfK)]2 by reacting NODAGA-E-[c(RGDfK)]2 with Al18F in sodium acetate buffer (pH ~4.1) for 15 min at 100°C. Radiochemical purity was >98% as determined with high-performance liquid chromatography, with an overall yield of 20%. The specific activity was 1.8 MBq/nmol (0.049 mCi/nmol) at the end of synthesis. The total synthesis time was <45 min. Al18F-NODAGA-E-[c(RGDfK)]2 had a logP value of −4.26 ± 0.02.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Dijkgraaf et al. (13) performed in vitro solid-phase binding assays of 111In-DOTA-E-[c(RGDfK)]2 with human αvβ3 integrin. NODAGA-E-[c(RGDfK)]2 had an IC50 value of 0.043 ± 0.037 nM. DOTA-E-[c(RGDfK)]2 had an IC50 value of 0.037 ± 0.085 nM.

Animal Studies

Rodents

[PubMed]

Dijkgraaf et al. (13) performed ex vivo biodistribution studies of 0.4 MBq (11 µCi) Al18F-NODAGA-E-[c(RGDfK)]2 with nude mice (n = 3–5/group) bearing SK-RC-52 human renal carcinoma tumors at 2 h after injection. The tumor accumulation was 3.4 ± 0.2% injected dose/gram (ID/g). The organ with the highest accumulation was the kidney (3.1% ID/g), followed by the intestine (2.8% ID/g), liver (1.5% ID/g), and spleen (1.5% ID/g). Low accumulation (<1% ID/g) was observed in the muscle, heart, lung, stomach, pancreas, and femur. Very low radioactivity was detected in blood (<0.1% ID/g). Coinjection of excess NODAGA-E-[c(RGDfK)]2 resulted in 75% reduction of radioactivity in the tumor (P < 0.001). The accumulation was also reduced in the liver, lung, intestine, stomach, femur, and spleen (this may be partly mediated by αvβ3 integrin in these tissues), but the kidney was not affected. PET scans showed that the tumor was clearly visualized at 2 h after injection of 10 MBq (0.27 mCi) Al18F-NODAGA-E-[c(RGDfK)]2. Some accumulation was observed in the kidneys. Coinjection of excess NODAGA-E-[c(RGDfK)]2 reduced radioactivity in the tumor but not in the kidneys. Similar findings of ex vivo and PET imaging studies were obtained with 68Ga-NODAGA-E-[c(RGDfK)]2. The ex vivo radioactivity levels of 68Ga-NODAGA-E-[c(RGDfK)]2 in the tumor (6.3 ± 0.8% ID/g) and intestine (~5.0% ID/g) were higher than those of Al18F-NODAGA-E-[c(RGDfK)]2 (3.4 ± 0.2% ID/g and 2.8% ID/g, respectively).

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., Terry S.Y., McBride W.J., Goldenberg D.M., Laverman P., Franssen G.M., Oyen W.J., Boerman O.C. Imaging integrin alpha-v-beta-3 expression in tumors with an (18) F-labeled dimeric RGD peptide. Contrast Media Mol Imaging. 2013;8(3):238–45. [PMC free article: PMC4034708] [PubMed: 23606427]
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