Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Epidermal growth factor

Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) 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, including 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 as well as 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 (7-10). Trastuzumab (a humanized immunoglobulin G (IgG) monoclonal antibody against the extracellular domain of recombinant HER2) (11) and C225 (an anti-EGFR, chimeric, monoclonal antibody) have been labeled as In-trastuzumab (12-14) and Tc-EC-C225 (15, 16) for imaging EGFR expression on solid tumors using single-photon emission computed tomography (SPECT). However, antibodies that are approximately 25-fold larger than EGF may not be easily transported to cells within solid tumors. Therefore, In-EGF and Tc-HYNIC-EGF have been developed for SPECT imaging studies of tumors (17, 18). However, positron emission tomography (PET) offers better sensitivity, resolution, and quantification than SPECT (19). Ga ( = 68 min, 89% β decay) is an attractive radionuclide for labeling EGF and is readily available from a commercial Ge/Ga generator. Cells retain Ga well, providing a good signal/background ratio. For evaluation as a PET imaging agent, Ga has been attached to EGF 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) to form Ga-DOTA-EGF (20).