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Dalton Transactions

The international journal for inorganic, organometallic and bioinorganic chemistry



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Dalton Trans., 2008, 3215 - 3225, DOI: 10.1039/b802021c

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

Célia Fernandes, Isabel C. Santos, I. Santos, Hans-Jurgen Pietzsch, Jens-Uwe Kunstler, Werner Kraus, Ana Rey, Nikos Margaritis, Athanasia Bourkoula, Aris Chiotellis, Maria Paravatou-Petsotas and Ioannis Pirmettis

The quinazoline derivatives (3-chloro-4-fluorophenyl)quinazoline-4,6-diamine ( 2) and (3-bromophenyl)quinazoline-4,6-diamine ( 3) were labelled with 99mTc 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 ( L1, L2) and by the tetradentate tripodal ligand tris(2-mercaptoethyl)-amine (NS3). In the 4 + 1 approach, 99mTc-labelling was performed in a two-step procedure, the complexes [Tc(NS3)( L1)] ( 7a) and [Tc(NS3)( L2)] ( 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 ( L5H) and the other contains a pyridine unit ( L6H). 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 99mTc-complexes ( 10a, 11a) being obtained in quantitative yield. The identities of the 99mTc-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 ( L1, L2) or to the pyrazolyl containing chelator ( L5H), 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 ( L6H) and corresponding Re complex ( 11), although to a lesser extent.

Graphical abstract image for this article (ID: b802021c)