Rhenium and technetium complexes bearing quinazoline derivatives:: progress towards a 99mTc biomarker for EGFR-TK imaging

The quinazoline derivatives ( 3- chloro- 4-fluorophenyl) quinazoline-4,6-diamine ( 2) and ( 3- bromophenyl) quinazoline- 4,6- diamine ( 3) were labelled with Tc-99m using the " 4 + 1" mixed- ligand system [ Tc( NS3)( CN- R)] and the tricarbonyl moiety fac-[ Tc( CO) 3]+. In the " 4 + 1" approach the technetium( III) is stabilized by a monodentate isocyanide bearing a quinazoline fragment (L-1, L-2) and by the tetradentate tripodal ligand tris( 2-mercaptoethyl)- amine (NS3). In the " 4 + 1" approach, Tc-99m- labelling was performed in a two-step procedure, the complexes [Tc(NS3)(L-1)] (7a) and [Tc(NS3)(L-2)] (8a) being obtained in about 50- 70% yield. In the tricarbonyl approach, the fac-[Tc(CO)(3)](+) unit is anchored by two different monoanionic chelators bearing the quinazoline derivatives ( 3- chloro- 4-fluorophenyl) quinazoline- 4,6- diamine ( 2) and ( 3- bromophenyl) quinazoline- 4,6- diamine ( 3). Both chelators have a N2O donor atom set, but one contains a pyrazolyl ring ( (LH)-H-5) and the other contains a pyridine unit ( (LH)-H-6). In both cases the conjugation of the quinazoline to the chelator was done through the secondary amine of the potentially tridentate and monoanionic chelators, the corresponding Tc-99m- complexes (10a, 11a) being obtained in quantitative yield. The identities of the Tc-99m- labelled quinazolines ( 7a, 8a, 10a, 11a) were confirmed by comparison with the HPLC profiles of the analogous Re compounds ( 7, 8, 10, 11). All these Re complexes were characterized by NMR and IR spectroscopy, elemental analysis and in some cases by MS and X-ray diffraction analysis. In vitro studies indicate that the quinazoline fragments, after conjugation to the cyano group ( L-1, L-2) or to the pyrazolyl containing chelator ( (LH)-H-5), as well as the corresponding Re complexes ( 7, 8, 10) inhibit significantly the EGFR autophosphorylation and also inhibit A431 cell growth. These two effects were also found for the pyridine-containing chelator ((LH)-H-6) and corresponding Re complex ( 11), although to a lesser extent.