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 (L¹1, L²2) 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)(L¹1)] (7a) and [Tc(NS₃)(L²2)] (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 (L⁵5H) and the other contains a pyridine unit (L⁶6H). 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 (L¹1, L²2) or to the pyrazolyl containing chelator (L⁵5H), 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 (L⁶6H) and corresponding Re complex (11), although to a lesser extent.

Novel ether-containing tris(pyrazolyl)methane chelators stabilize the fac-[^99mTc(CO)₃]⁺ moiety providing complexes with significant, fast and stable heart uptake, together with a extremely fast liver clearance.