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 (99m)Tc 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.
Fernandes
Célia
C
Departamento de Química, ITN, Estrada Nacional 10, Sacavém Codex, Portugal.
Santos
Isabel C
IC
Santos
I
I
Pietzsch
Hans-Jurgen
HJ
Kunstler
Jens-Uwe
JU
Kraus
Werner
W
Rey
Ana
A
Margaritis
Nikos
N
Bourkoula
Athanasia
A
Chiotellis
Aris
A
Paravatou-Petsotas
Maria
M
Pirmettis
Ioannis
I
D015415:Biomarkers / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D015415:Biomarkers; D002614:Chelating Agents; D015609:Organotechnetium Compounds; D011799:Quinazolines; D004815:Epidermal Growth Factor; D012211:Rhenium; C512478:EGFR protein, human; D066246:ErbB Receptors