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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-Diamine dioxime-Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys-polyethylene glycol

99mTc-NC100692
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: May 20, 2010.

Chemical name:99mTc-Diamine dioxime-Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys-polyethylene glycol
Abbreviated name:99mTc-NC100692
Synonym:
Agent category:Peptide
Target:Integrin αvβ3
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT)
Source of signal:99mTc
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
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 on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues (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 cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to αvβ3 integrin (50% inhibition concentration (IC50), 7–40 nM) but no inhibition of binding to αvβ5 (IC50, 600–4,000 nM) or αIIbβ3 (IC50, 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Of these developments, [18F]galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of αvβ3 integrin in cancer patients (14-19). Both αvβ3 and αvβ5 integrins bind to vitronectin (20). However, while the αvβ3 integrin is required for basic fibroblast growth factor–mediated angiogenesis, the αvβ5 integrin is required for vascular endothelial growth factor–induced angiogenesis (21, 22). The peptide Lys-Cys-Arg-Gly-Asp-Cyc-Phe-Cys (NC100717) was identified with phage display screening to be a potent and selective binder to both αvβ3 and αvβ5 integrins (23). A new peptide, NC100692, was derived from NC100717 with addition of diamine dioxime to the ε-amine of Lys and the N-terminal end modified with a short polyethylene glycol unit. Hua et al. (24) reported the development of 99mTc-NC100692 for single-photon emission computed tomography (SPECT) imaging of αvβ3 and αvβ5 integrins in mice with hindlimb ischemia. Bach-Gansmo et al. (25) has performed a preliminary study in patients with breast cancer.

Synthesis

[PubMed]

NC100692 was prepared with solid-phase Fmoc chemistry. Edwards et al. (26) prepared 99mTc-NC100692 using labeling kits containing 44 nmol NC100692. 99mTc-Pertechnetate was added for in vivo (2.1 GBq (56 mCi)) and in vitro (100 GBq (2.7 Ci)) binding studies. The radiochemical purity was >90% within 1 h of reconstitution. The specific activities were not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Indrevoll et al. (23) performed in vitro binding assays of 125I-echistatin with EA-Hy926 cell membranes containing αvβ3 and αvβ5 integrins. NC100717 and NC100692 had Ki (inhibition constant) values of 1.6 ± 1.6 and 3.1 ± 1.6 nM, respectively. Edwards et al. (26) showed that Kd (binding constant) values of 99mTc-NC100692 for αvβ3 and αvβ5 integrins were 0.5 ± 0.01 and 0.1 ± 0.04 nM, respectively. No specific binding was observed for α1β1, α3β1, αvβ1, and αIIbβ5 integrins.

Animal Studies

Rodents

[PubMed]

Hua et al. (24) performed pinhole planar imaging studies of 99mTc-NC100692 in mice with hindlimb ischemia (n = 5–9/group) as an established model of angiogenesis. Mice with femoral occlusion were injected with 55.5 MBq (1.5 mCi) 99mTc-NC100692 on days 1, 3, 7, and 14 of ischemia. Static images were obtained 75 min after 99mTc-NC100692 injection. A significant increase (P < 0.05) in the ischemia/non-ischemia ratio was observed on days 3 (1.5 ± 0.7) and 7 (1.6 ± 0.8) versus the control group (0.9 ± 0.1). 99mTc-NC100692 was cleared quickly from the blood through the kidneys. Ex vivo analysis of excised tissues showed that these ratios were similar to those observed with the in vivo imaging. Immunohistochemistry showed a significant increase (P < 0.05) in RGD staining with endothelial cells within the ischemic hindlimb as compared with the contralateral control hindlimb at days 3, 7, and 14. No blocking experiment was performed.

Edwards et al. (26) performed ex vivo biodistribution studies of 99mTc-NC100692 with normal rats (n = 3/group) at 2, 20, 60, and 240 min after injection. Radioactivity was quickly excreted into urine with little accumulation in other tissues except for the liver and kidneys. The accumulation in the liver and kidneys was reduced with coinjection of NC100692 with the tracer. There was little systemic metabolism of 99mTc-NC100692 up to 20 min after injection. Blood clearance of 99mTc-NC100692 was rapid, and the intact molecule was not detectable at 60 min after injection.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Bach-Gansmo et al. (25) studied 16 breast cancer patients with suggestive mammographic findings and 4 breast cancer patients with benign lesions as determined with 99mTc-NC100692 scintigraphy. All patients received ~700 MBq (19 mCi) 99mTc-NC100692, with 5 patients experiencing non-serious adverse events. Nineteen of 22 (86%) malignant lesions >7 mm in diameter were detected. In another study, Bach-Gansmo et al. (27) performed scintimammography with 99mTc-NC100692 and a dedicated γ-camera, which revealed 9 of 11 lesions (6–20 mm in diameter) in 8 patients with a high suspicion of breast cancer.

References

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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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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]
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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]
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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]
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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]
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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]
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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.
Haubner R., Weber W.A., Beer A.J., Vabuliene E., Reim D., Sarbia M., Becker K.F., Goebel M., Hein R., Wester H.J., Kessler H., Schwaiger M. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2(3):e70. [PMC free article: PMC1069665] [PubMed: 15783258]
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Silva R., D'Amico G., Hodivala-Dilke K.M., Reynolds L.E. Integrins: the keys to unlocking angiogenesis. Arterioscler Thromb Vasc Biol. 2008;28(10):1703–13. [PubMed: 18658045]
21.
Friedlander M., Brooks P.C., Shaffer R.W., Kincaid C.M., Varner J.A., Cheresh D.A. Definition of two angiogenic pathways by distinct alpha v integrins. Science. 1995;270(5241):1500–2. [PubMed: 7491498]
22.
Hood J.D., Cheresh D.A. Targeted delivery of mutant Raf kinase to neovessels causes tumor regression. Cold Spring Harb Symp Quant Biol. 2002;67:285–91. [PubMed: 12858551]
23.
Indrevoll B., Kindberg G.M., Solbakken M., Bjurgert E., Johansen J.H., Karlsen H., Mendizabal M., Cuthbertson A. NC-100717: a versatile RGD peptide scaffold for angiogenesis imaging. Bioorg Med Chem Lett. 2006;16(24):6190–3. [PubMed: 17000103]
24.
Hua J., Dobrucki L.W., Sadeghi M.M., Zhang J., Bourke B.N., Cavaliere P., Song J., Chow C., Jahanshad N., van Royen N., Buschmann I., Madri J.A., Mendizabal M., Sinusas A.J. Noninvasive imaging of angiogenesis with a 99mTc-labeled peptide targeted at alphavbeta3 integrin after murine hindlimb ischemia. Circulation. 2005;111(24):3255–60. [PubMed: 15956134]
25.
Bach-Gansmo T., Danielsson R., Saracco A., Wilczek B., Bogsrud T.V., Fangberget A., Tangerud A., Tobin D. Integrin receptor imaging of breast cancer: a proof-of-concept study to evaluate 99mTc-NC100692. J Nucl Med. 2006;47(9):1434–9. [PubMed: 16954550]
26.
Edwards D., Jones P., Haramis H., Battle M., Lear R., Barnett D.J., Edwards C., Crawford H., Black A., Godden V. 99mTc-NC100692--a tracer for imaging vitronectin receptors associated with angiogenesis: a preclinical investigation. Nucl Med Biol. 2008;35(3):365–75. [PubMed: 18355693]
27.
Bach-Gansmo T., Bogsrud T.V., Skretting A. Integrin scintimammography using a dedicated breast imaging, solid-state gamma-camera and (99m)Tc-labelled NC100692. Clin Physiol Funct Imaging. 2008;28(4):235–9. [PubMed: 18384623]

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