title: Radioiodinated sunitinib as a potential radiotracer for imaging angiogenesis-radiosynthesis and first radiopharmacological evaluation of 5-[125I]Iodo-sunitinib.
abstract: Sunitinib® (SU11248) is a highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR). Radiolabeled inhibitors of RTKs might be useful tools for monitoring RTKs levels in tumour tissue giving valuable information for anti-angiogenic therapy. We report here the synthesis of a (125)I-labeled derivative of sunitinib® and its first radiopharmaceutical characterization. The non-radioactive reference compound 5-iodo-sunitinib 4 was prepared by Knoevenagel condensation of 5-iodo-oxindole with the corresponding substituted 5-formyl-1H-pyrrole. In a competition binding assay against VEGFR-2 a binding constant (K(d)) of 16 nM for 4 was found. The ability of 4 to inhibit tyrosine kinase activity was demonstrated on RTK expressing cells suggesting this radiotracer as a useful tool for monitoring VEGFR expression. 5-[(125)I]lodo-sunitinib, [(125)I]-4 was obtained via destannylation of the corresponding tributylstannyl precursor with [(125)I]NaI in the presence of H(2)O(2) in high radiochemical yield (>95%) and radiochemical purity (<98%) after HPLC purification. Determination of human plasma protein binding at time intervals of 0; 1; 2; 4 and 24h suggested a low non-specific binding of 5-10%. Preliminary biodistribution studies of [(125)I]-4 in healthy CD-1 mice showed a relatively high uptake in VEGFR-2 rich tissues like kidney and lung followed by rapid washout (9.6 and 9.7; 4.5 and 3.8% ID/g of kidney and lung at 1 and 4h, respectively).
authors.affiliation: Institute of Radiopharmacy, Helmholtz-Zentrum Dresden-Rossendorf eV, POB 510119, Dresden, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Kuchar
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Oliveira
authors.forename: Lurdes
authors.initials: L
authors.lastname: Gano
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007457:Iodine Radioisotopes; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D000078183:Oxindoles; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000077210:Sunitinib
chemical_list: C574958:5-(125I)iodo-sunitinib; D020533:Angiogenesis Inhibitors; D007211:Indoles; D007457:Iodine Radioisotopes; D000078183:Oxindoles; D011758:Pyrroles; D019275:Radiopharmaceuticals; D000077210:Sunitinib