Abstract
The epidermal growth factor receptor (EGFR) is overexpressed in many cancers, including breast, ovarian, endometrial and non-small cell lung cancer. An EGFR-specific imaging agent could facilitate clinical evaluation of primary tumors or metastases. To achieve this goal, 4-(2-aminoethylamino)-6,7-dimethoxyquinazoline (ADMQ) was synthesized based on a 4-aminoquinazoline core and then conjugated with N-mercapto- acetylglycine (MAG) and N-mercaptoacetyltriglycine (MAG3), respectively, to give compounds 1 and 2. The final complexes [99mTcN]-1 and [99mTcN]-2 were successfully obtained with radiochemical purities of >99% and >98% as measured by radio-HPLC. No decomposition of the two complexes at room temperature was observed over a period of 2 h. Their partition coefficients indicated they were hydrophilic and the electrophoresis results showed they were negatively charged. Biodistribution in tumor-bearing mice demonstrated that the two new complexes showed tumor accumulation, high tumor-tomuscle (T/M) ratios and fast clearance from blood and muscle. Between the two compounds, the 99mTcN-MAG3-ADMQ ([99mTcN]-2) showed the better characteristics, with the tumor/muscle and tumor/blood ratios reached 2.11 and 1.90 at 60 min post-injection, 4.20 and 1.10 at 120 min post-injection, suggesting it could be a promising radiotracer for SPECT tumor imaging.
Highlights
Epidermal growth factor receptor (EGFR) is a member of the epidermal growth factor (EGF) family of tyrosine kinase receptors
The synthesis of 4-(2-aminoethylamino)-6,7-dimethoxyquinazoline was carried out using the procedure shown in Scheme 1
Biodistribution studies of the two complexes were performed in Kunming female mice (18–22 g) bearing S 180 tumors, which grew to a leg diameter of 10–15 mm. 99mTcN-mercapto- acetylglycine (MAG)-ADMQ, and
Summary
Epidermal growth factor receptor (EGFR) is a member of the epidermal growth factor (EGF) family of tyrosine kinase receptors (which includes ErbB2, ErbB3 and ErbB4). The activated receptor can dimerize with other EGFRs followed by phosphorylation of tyrosine residues on the receptors This active conformation makes it possible for TK domain of the receptors both to bind ATP and to transphosphorylate each other [3,4]. Receptor autophosphorylation on tyrosine residues both enhances the activity of kinases and provides docking sites for downstream signal transduction molecules that habor SH2 or PTB domains. These interaction activate signal transduction pathways, which lead to multiple cellular processes, such as proliferation, differentiation, apotosis, angiogenesis, cell adhesion and movement [5,6,7]. TcN-MAG-ADMQ ([99mTcN]-1) and 99mTcN-MAG3-ADMQ ([99mTcN]-2) were designed and synthesized to evaluate the feasibility of the 99mTc-labeled 4-aminoquinazoline derivatives as useful candidates for tumor imaging
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