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

[摘要]：Aiming at the development of technetium-99m (Tc-99m) 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-[(TC)-T-99m(CO)(3)](+) core as an N,N bidentate ligand. The labelling was performed in high yield (>90%) by ligand exchange reaction using fac-[Tc-99m(OH2)(3)CO)(3)](+) as precursor. The Tc-99m 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 mu M respectively). Biodistribution of the Tc-99m 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. (C) 2009 Elsevier Masson SAS. All rights reserved.

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