title: Synthesis and characterization of rhenium and technetium-99m tricarbonyl complexes bearing the 4-[3-bromophenyl]quinazoline moiety as a biomarker for EGFR-TK imaging.
abstract: Aiming at the development of technetium-99m ((99m)Tc) 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-[(99m)Tc(CO)(3)](+) core as an N,N bidentate ligand. The labelling was performed in high yield (>90%) by ligand exchange reaction using fac-[(99m)Tc(OH(2))(3)(CO)(3)](+) as precursor. The (99m)Tc 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-[ReBr(3)(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 (IC(50): 17+/-3.7 and 114+/-23 nM respectively) in intact A431 cells, bind the receptor in a reversible mode, and inhibit A431 cell growth (IC(50): 5.2+/-1.1 and 2.0+/-0.98 microM respectively). Biodistribution of the (99m)Tc 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.
authors.affiliation: Institute of Radioisotopes-Radiodiagnostic Products, National Centre for Scientific Research Demokritos, 15310 Athens, Greece.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Bourkoula
authors.forename: Maria
authors.initials: M
authors.lastname: Paravatou-Petsotas
authors.forename: Apostolos
authors.initials: A
authors.lastname: Papadopoulos
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Hans-Jurgen
authors.initials: HJ
authors.lastname: Pietzsch
authors.forename: Evangelia
authors.initials: E
authors.lastname: Livaniou
authors.forename: Maria
authors.initials: M
authors.lastname: Pelecanou
authors.forename: Minas
authors.initials: M
authors.lastname: Papadopoulos
authors.forename: Ioannis
authors.initials: I
authors.lastname: Pirmettis
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012211:Rhenium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014846:Vulvar Neoplasms / Q000188:drug therapy
chemical_list: D014408:Biomarkers, Tumor; D015609:Organotechnetium Compounds; D011799:Quinazolines; D012211:Rhenium; C512478:EGFR protein, human; D066246:ErbB Receptors