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68Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)]2

68Ga-DOTA-E-[c(RGDfK)]2
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: May 12, 2011.

Chemical name:68Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)]2image 117703375 in the ncbi pubchem database
Abbreviated name:68Ga-DOTA-E-[c(RGDfK)]2
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 the above structure for additional information in PubChem.

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 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). Janssen et al. (13) reported the development of 111In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)]2 (111In-DOTA-E-[c(RGDfK)]2) for single-photon emission computed tomography imaging αvβ3 receptors in nude mice bearing ovarian carcinoma tumors. Dijkgraaf et al. (14) also reported the evaluation of 68Ga-DOTA-E-[c(RGDfK)]2 for positron emission tomography (PET) imaging αvβ3 receptors in tumor, which is the topic of this chapter.

Synthesis

[PubMed]

Dijkgraaf et al. (14) prepared the synthesis of 68Ga-DOTA-E-[c(RGDfK)]2 by reacting DOTA-E-[c(RGDfK)]2 with 68Ga in ammonium acetate buffer (pH ~5.5) at 95°C for 20 min. Radiochemical purity was ~98% as determined by high-performance liquid chromatography. The maximum specific activity was 11.2 MBq/nmol (0.3 mCi/nmol). 68Ga-DOTA-E-[c(RGDfK)]2 was stable in phosphate-buffered saline and human serum at 37°C for 2 h.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Dijkgraaf et al. (14) performed in vitro solid-phase binding assays of 111In-DOTA-E-[c(RGDfK)]2 with human αvβ3 integrin. natGa-DOTA-E-c(RGDfK) (monomer) had an IC50 value of 23.9 ± 1.22 nM. natGa-DOTA-E-[c(RGDfK)]2 (dimer) had an IC50 value of 8.99 ± 1.20 nM. natGa-DOTA-E-{E-[c(RGDfK)]2}2 (tetramer) had an IC50 value of 1.74 ± 1.18 nM.

Animal Studies

Rodents

[PubMed]

Dijkgraaf et al. (14) performed ex vivo biodistribution studies of 68Ga-DOTA-E-[c(RGDfK)]2 in nude mice (n = 3/group) bearing SK-RC-52 human renal carcinoma tumors at 2 h after injection. The tumor accumulation was 5.2 ± 0.3% injected dose/gram (ID/g). The organ with the highest accumulation was the intestine (~5% ID/g), followed by the kidney (~4% ID/g), spleen (~3% ID/g), liver (~2% ID/g) and colon (~2% ID/g). Coinjection of 100-fold excess DOTA-E-[c(RGDfK)]2 resulted in >90% reduction of radioactivity in the tumor. The accumulation was also markedly reduced in the liver, lung, intestine, colon and spleen (this may be partly mediated by αvβ3 integrin in these tissues) but not in the kidney. PET scan showed that the tumor was clearly visualized at 2 h after injection of 10 MBq (0.27 mCi) 68Ga-DOTA-E-[c(RGDfK)]2. Some accumulation was observed in the kidneys.

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.
Janssen M.L., Oyen W.J., Dijkgraaf I., Massuger L.F., Frielink C., Edwards D.S., Rajopadhye M., Boonstra H., Corstens F.H., Boerman O.C. Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model. Cancer Res. 2002;62(21):6146–51. [PubMed: 12414640]
14.
Dijkgraaf I., Yim C.B., Franssen G.M., Schuit R.C., Luurtsema G., Liu S., Oyen W.J., Boerman O.C. PET imaging of alphavbeta integrin expression in tumours with Ga-labelled mono-, di- and tetrameric RGD peptides. Eur J Nucl Med Mol Imaging. 2011;38(1):128–37. [PMC free article: PMC3005123] [PubMed: 20857099]

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