Synthesis and characterization of rhenium and technetium-99m tricarbonyl complexes bearing the 4-[3-bromophenyl]quinazoline moiety as a biomarker for EGFR-TK imaging

Aiming at the development of technetium-99m (^99mTc) complexes for early detection and staging of EGFR positive tumors, the tyrosine kinase inhibitor 6-amino-4-[(3-bromophenyl)amino]quinazoline was derivatized with pyridine-2-carboxaldehyde to generate the imine 6-(pyridine-2-methylimine)-4-[(3-bromophenyl) amino]quinazoline suitable for reacting with the fac-[^99mTc(CO)₃]⁺ core as an N,N bidentate ligand. The labelling was performed in high yield (>90%) by ligand exchange reaction using fac-[^99mTc(OH₂)₃(CO)₃]⁺ as precursor. The ^99mTc complex was characterized by comparative HPLC analysis using the analogous rhenium (Re) complex as reference. The Re complex was prepared by ligand exchange reaction using the fac-[ReBr₃(CO)₃]^2- as precursor and was fully characterized by NMR and IR spectroscopies and elemental analysis. In vitro studies indicate that both the ligand and its Re complex
inhibit the EGFR autophosphorylation (IC50: 17± 3.7 and 114 ± 23 nM respectively) in intact A431 cells, bind the receptor in a reversible mode, and inhibit A431 cell growth (IC50: 5.2 ± 1.1 and 2.0 ± 0.98 µM respectively). Biodistribution of the ^99mTc complex in healthy animals showed a rather fast blood and soft tissue clearance between 1 and 15 min p.i. with excretion occurring mainly via the hepatobiliary system.