Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer

• Published in: Bioorganic & medicinal chemistry 2007-06, Vol.15 (12), p.3974-3980
• Main Authors: Fernandes, Célia, Oliveira, Cristina, Gano, Lurdes, Bourkoula, Athanasia, Pirmettis, Ioannis, Santos, Isabel
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blood Proteins - metabolism; Breast Neoplasms - diagnostic imaging; Cancer; Cell Line, Tumor; Chromatography, High Pressure Liquid; Contrast media. Radiopharmaceuticals; EGFR; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - isolation & purification; Enzyme Inhibitors - metabolism; Humans; Iodine Radioisotopes - chemistry; Medical sciences; Pharmacology. Drug treatments; Phosphorylation; Quinazoline; Quinazolines - chemistry; Quinazolines - isolation & purification; Quinazolines - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; SPECT; Tomography, Emission-Computed, Single-Photon; Tyrosine kinase inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.04.008

[ 125I]- N-{4-[(3-Chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide ([ 125 I]- 7), a potential EGFR-TK inhibitor, was synthesised from 4-hydroxyquinazoline 1 and was in vitro evaluated for inhibitory activity of EGFR. In our search for the development of novel SPECT radioligands for EGFR positive tumours, new potentially irreversible tyrosine kinase (TK) inhibitors are being explored. The radioiodination of N-{4-[(3-chloro-4-fluorophenyl) amino]quinazoline-6-yl}-3-bromopropionamide, a novel EGFR-TK inhibitor synthesised in our laboratory, was accomplished via halogen exchange. Purification by RP-HPLC gave [ 125I]- N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide with a radiochemical purity higher than 95% and a high specific activity. In vitro studies indicate that both iodinated quinazoline and its bromo precursor inhibit A431 cell growth and also possess higher potency than the parent quinazoline to inhibit the EGFR autophosphorylation. In vivo stability studies suggest metabolization of the radioiodinated quinazoline indicating a short biological half-life. The in vitro results point out that these quinazoline derivatives could be promising candidates for SPECT imaging of EGFR positive tumours provided that they are selectively modified in order to achieve better in vivo radiochemical stability.