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64Cu-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-(Gly-Ser-Gly)-Lys-Cys-Cys-Tyr-Ser-Leu.

Authors

Leung K.

Source

Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2012 Apr 26 [updated 2012 Jul 05].

Excerpt

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-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-(Gly-Ser-Gly)-Lys-Cys-Cys-Tyr-Ser-Leu (64Cu-CB-TE2A-(GSG)-KCCYSL) for imaging of HER2 expression in breast tumors.

PMID:
22787683
[PubMed]
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