title: Synthesis and radiopharmacological investigation of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one as possible tyrosine kinase inhibitor.
abstract: The radiosynthesis and radiopharmacological evaluation of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one, a derivative of tyrosine kinase inhibitor SU5416, is described. The radiosynthesis was accomplished by Knoevenagel condensation of 4-[(18)F]fluorobenzaldehyde with oxindole in a remotely controlled synthesis module. The reaction conditions were optimized through screening the influence of different bases on the radiochemical yield. The radiotracer was obtained after a two-step labelling procedure in 4% decay-corrected radiochemical yield at a specific activity of 48-61GBq/micromol within 90min. The radiochemical purity after semi-preparative HPLC purification exceeded 98%. The biodistribution was studied in Wistar rats. After distribution the radiotracer was rapidly accumulated in the adrenals, liver and kidneys, however, it was cleared from these and the most other organs. Only the adipose tissue remained the activity over 60min. Unexpected high transient uptake was observed in the brain, pancreas, heart and lung. The fast clearance of 3-[4'-[(18)F]fluorobenzylidene]indolin-2-one was caused by excretion, approximately one half each was renal and biliary excreted and the other part cleared by metabolic processes. In arterial blood plasma two more polar metabolites were found by radio-HPLC. After 20min post-injection, only 12% of intact radiotracer has been detected. Consequently, in small animal PET studies with FaDu tumour bearing mice no specific uptake in the tumours could be observed.
authors.affiliation: Institute of Radiopharmacy, Forschungszentrum Dresden-Rossendorf e.V., PO Box 510119, D-01314 Dresden, Germany. t.kniess@fzd.de
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Manuela
authors.initials: M
authors.lastname: Kuchar
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051379:Mice; D008956:Models, Chemical; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011758:Pyrroles; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: C546690:3-(4'-fluorobenzylidene)indolin-2-one; D005462:Fluorine Radioisotopes; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D019275:Radiopharmaceuticals; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases