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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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64Cu-1,4,7-Triazacyclononane-1,4-diacetic acid-(Gly-Ser-Gly)-Lys-Cys-Cys-Tyr-Ser-Leu

64Cu-NO2A-(GSG)-KCCYSL
, PhD
National Center for Biotechnology Information, NLM, NIH

Created: ; Last Update: July 5, 2012.

Chemical name:64Cu-1,4,7-Triazacyclononane-1,4-diacetic acid-(Gly-Ser-Gly)-Lys-Cys-Cys-Tyr-Ser-Leu
Abbreviated name:64Cu-NO2A-(GSG)-KCCYSL
Synonym:
Agent category:Peptide
Target:Epidermal growth factor receptor-2 (EGFR-2, HER2)
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 HER2.

Background

[PubMed]

Epidermal growth factor (EGF) is a growth factor composed of 53 amino acids (6.2 kDa), and it is secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors: EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2; however, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 and HER2 are overexpressed on many solid tumor cells, such as breast, non-small cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor prognosis because high levels are related to increased proliferation (7-10).

Trastuzumab is a humanized IgG1 monoclonal antibody (mAb) against the extracellular domain of recombinant HER2 with an affinity constant (Kd) of 0.1 nM (11). 111In-Trastuzumab, Cy5.5-trastuzumab, and 68Ga-trastuzumab-F(ab')2 have been developed for imaging of human breast cancer (12-16). However, the pharmacokinetics of intact radiolabeled mAbs, with high liver uptake and slow blood elimination, are generally not ideal for imaging. Smaller antibody fragments, such as Fab or F(ab')2, have better imaging pharmacokinetics because they are rapidly excreted by the kidneys. A setapeptide sequence consisting of Lys-Cys-Cys-Tyr-Ser-Leu (KCCYSL) was identified using phage display screening to bind specifically to the extracellular domain of HER2 (17). 111In-1,4,7,10-Tetraazacyclododecane-1,4,7-tris-acetic acid-(Gly-Ser-Gly)-Lys-Cys-Cys-Tyr-Ser-Leu (111In-DOTA-(GSG)-KCCYSL) was evaluated in nude mice bearing human breast tumor xenografts for single-photon emission computed tomography imaging (18). For positron emission tomography (PET), Kumar et al. (19) prepared 64Cu-1,4,7-triazacyclononane-1,4-diacetic acid-(Gly-Ser-Gly)-Lys-Cys-Cys-Tyr-Ser-Leu (64Cu-NO2A-(GSG)-KCCYSL) for imaging of HER2 expression in breast tumors.

Synthesis

[PubMed]

GSG-KCCYSL peptides were prepared with solid-phase peptide synthesis (19). The metal chelator NOTA was coupled to the amino terminus of GSG-KCCYSL with solid-phase synthesis. NO2A-(GSG)-KCCYSL was purified with high-performance liquid chromatography (HPLC). The chemical purity of NO2A-(GSG)-KCCYSL was 98%. NO2A-(GSG)-KCCYSL (37.6 nmol) was mixed with 29.6 MBq (0.80 mCi) 64Cu in ammonium acetate (pH 6.4) and incubated for 60 min at 75°C. 64Cu-NO2A-(GSG)-KCCYSL was purified with HPLC, with >98% radiochemical purity and 57% labeling yield. The specific activity of 64Cu-NO2A-(GSG)-KCCYSL was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Kumar et al. (19) performed in vitro binding assays of 64Cu-NO2A-(GSG)-KCCYSL binding to human MDA-MB-435 breast carcinoma cells that express HER2 receptors. natCu-NO2A-(GSG)-KCCYSL exhibited a IC50 value of 44 ± 7 nM (n = 3). 64Cu-NO2A-(GSG)-KCCYSL accumulated in MDA-MB-435 cells in a time-dependent manner at 37°C with a plateau at 45 min, whereas little radioactivity was observed in normal human mammary epithelial cells (184A1) that express low levels of HER2 receptors. 64Cu-NO2A-(GSG)-KCCYSL was stable in mouse serum at 37°C after up to 2 h of incubation with some degradation at 4–24 h.

Animal Studies

Rodents

[PubMed]

Kumar et al. (19) performed ex vivo biodistribution studies with 0.185 MBq (5 μCi) 64Cu-NO2A-(GSG)-KCCYSL in SCID mice (n = 3/group) bearing MDA-MB-435 xenografts at 0.5, 1, 2, and 4 h after injection. The tumor accumulation of radioactivity at 0.5 h after injection was 0.78 ± 0.03% injected dose/gram (ID/g) and decreased to 0.43 ± 0.02% ID/g at 4 h. High accumulation levels were observed in the kidneys (4.23 ± 1.00% ID/g), lung (0.49 ± 0.07% ID/g), and liver (0.48 ± 0.05% ID/g) at 2 h after injection. The tumor/blood, tumor/muscle, and tumor/liver ratios were 7.6, 10.7, and 1.3 at 2 h after injection, respectively. Pretreatment (10 min) with natCu-NO2A-(GSG)-KCCYSL (76 nmol/mouse) inhibited the tumor radioactivity by 50% at 2 h after injection. Little inhibition was observed in the normal tissues. In comparison, 64Cu-NO2A-(GSG)-KCCYSL exhibited lower retention in the liver and higher tumor/nontarget tissue ratios than 64Cu-DO3A-(GSG)-KCCYSL, which exhibited liver accumulation of 1.68 ± 0.42% ID/g and tumor/blood, tumor/muscle, and tumor/liver ratios of 2.7, 9.0, and 0.3 at 2 h after injection, respectively.

PET analysis was performed in SCID mice (the number of mice was not reported) bearing the MDA-MB-435 tumors at 2 h after injection of 12 MBq (0.32 mCi) 64Cu-NO2A-(GSG)-KCCYSL (19). The tumors were clearly visualized along with 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.

NIH support

P50 CA103130-01, IR21 CA137239-01A1, 2 R01 CA093375

References

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Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61 Suppl 2:1–13. [PubMed: 11694782]
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Carter P., Presta L., Gorman C.M., Ridgway J.B., Henner D., Wong W.L., Rowland A.M., Kotts C., Carver M.E., Shepard H.M. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89(10):4285–9. [PMC free article: PMC49066] [PubMed: 1350088]
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Garmestani K., Milenic D.E., Plascjak P.S., Brechbiel M.W. A new and convenient method for purification of 86Y using a Sr(II) selective resin and comparison of biodistribution of 86Y and 111In labeled Herceptin. Nucl Med Biol. 2002;29(5):599–606. [PubMed: 12088731]
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Smith-Jones P.M., Solit D.B., Akhurst T., Afroze F., Rosen N., Larson S.M. Imaging the pharmacodynamics of HER2 degradation in response to Hsp90 inhibitors. Nat Biotechnol. 2004;22(6):701–6. [PubMed: 15133471]
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Karasseva N.G., Glinsky V.V., Chen N.X., Komatireddy R., Quinn T.P. Identification and characterization of peptides that bind human ErbB-2 selected from a bacteriophage display library. J Protein Chem. 2002;21(4):287–96. [PubMed: 12168699]
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Deutscher S.L., Figueroa S.D., Kumar S.R. In-labeled KCCYSL peptide as an imaging probe for ErbB-2-expressing ovarian carcinomas. J Labelled Comp Radiopharm. 2009;52(14):583–590. [PMC free article: PMC2957019] [PubMed: 20976123]
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Kumar S.R., Gallazzi F.A., Ferdani R., Anderson C.J., Quinn T.P., Deutscher S.L. In vitro and in vivo evaluation of Cu-radiolabeled KCCYSL peptides for targeting epidermal growth factor receptor-2 in breast carcinomas. Cancer Biother Radiopharm. 2010;25(6):693–703. [PMC free article: PMC3026654] [PubMed: 21204764]
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