Κατεύθυνση Σχεδιασμός και Ανάπτυξη νέων Φαρμακευτικών Ενώσεων - Ραδιοφαρμακευτική ΧημείαLibrary of the School of Science
Τσοτίνης Ανδρέας, Καθηγητής Φαρμακευτικής Χημείας, Τμήμα Φαρμακευτικής, Εθνικό Καποδιστριακό Πανεπιστήμιο Αθηνών
ΣΥΝΘΕΣΗ ΚΑΙ ΑΞΙΟΛΟΓΗΣΗ ΣΥΜΠΛΟΚΩΝ ΤΟΥ Re ΚΑΙ ΤΟΥ 99mTc ΜΕ ΚΙΝΑΖΟΛΙΝΙΚΑ ΠΑΡΑΓΩΓΑ ΓΙΑ ΤΗ ΣΤΟΧΕΥΣΗ ΤΟΥ EGFR
SYNTHESIS AND EVALUATION OF Re AND 99mTc COMPLEXES WITH QUINAZOLINE DERIVATIVES FOR EGFR TARGETING
Aiming at the development of labeled quinazoline derivatives for EGFR imaging, it is reported herein the synthesis and characterization of novel neutral rhenium and technetium complexes of the general formula fac–[M(CO)3L1/2], where Μ=Re or 99mTc. EGFR is overexpressed in many tumors, related with poor response in therapy and poor survival. Therefore, the development of drugs targeting the EGFR receptor has already progressed. Labeling small molecules of EGFR tyrosine kinase inhibitors using the metal core fac– [99mTc (CO)3 ]+, due to 99mTc ideal properties for SPECT imaging, has also gained increased interest. In this thesis, the pharmacophore quinazoline derivative, coupled with picolinamine-N-ethyl acetate (PAMA) or propylene–S–cysteine moiety, were synthesized and characterized. PAMA and cysteine moieties bear the suitable donor system (NNO for PAMA and SNO for cysteine) which stabilizes the metal core fac–[M(I)(CO)3] + (M = Re or 99mTc), acting as tridentate ligands and forming neutral complexes. The rhenium complexes were synthesized using the organometallic precursor [ReBr(CO)5] or [NEt4]2[Re(CO)3Br3] and characterized by IR and 1H–NMR. The respective technetium–99m complexes were synthesized, in high yield (>90%), using the cationic precursor fac–[99mTc(CO)3(H2O)3]+ and were characterized by comparative HPLC, using the respective characterized rhenium complexes as reference. Stability studies showed that the 99mTc complexes are stable in their reaction mixture and after isolation by HPLC for at least 24 hours. Histidine and cysteine challenge experiments showed high stability up to 95%. Lipophilicity studies suggest high lipophilicity for both complexes. The values of logP are 3.27 and 2.87 and as expected the highest value belongs to the complex bearing the pyridine ring of the PAMA chelator. The tridentate ligands and their rhenium complexes were studied for their cytotoxicity against the human cell line, A431 (epidermoid) by the MTT method. The cytotoxicity of the complex bearing the PAMA moiety is higher (IC50 =8.85 ± 2.62 μM) than that of complex bearing the SNO donor system (IC50 =29.56 ± 3.63 μM). Based on cytotoxicity experiments of quinazoline derivatives taken place over the last years, it can be concluded that the elongation of the spacer between the chelator and the 4–anilinoquinazoline pharmacophore improves the cytotoxicity. As far as the in vivo biological distribution is concerned, it was performed in healthy Swiss Albino mice. Both 99mTc complexes present fast blood clearance. There was not significant uptake to normal tissues and the complexes are showed to be excreted by the hepatobiliary system.
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Other subject categories:
rhenium, technetium, quinazolines, EGFR, radiopharmaceuticals
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