RESUMEN
Synthesis and in vitro evaluation of [(18)F](R)-N-(4-bromo-2-fluorophenyl)-7-((1-(2-fluoroethyl)piperidin-3-yl)methoxy)-6-methoxyquinazolin-4-amine ((R)-[(18)F]FEPAQ or [(18)F]1), a potential imaging agent for the VEGFR2, using phosphor image autoradiography are described. Synthesis of 2, the desfluoroethyl precursor for (R)-FEPAQ was achieved from t-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (3) in five steps and in 50% yield. [(18)F]1 was synthesized by reaction of sodium salt of compound 2 with [(18)F]fluoroethyl tosylate in DMSO. The yield of [(18)F]1 was 20% (EOS based on [(18)F]F(-)) with >99% radiochemical purity and specific activity of 1-2 Ci/µmol (n=10). The total synthesis time was 75 min. The radiotracer selectively labeled VEGFR2 in slide-mounted sections of human brain and higher binding was found in surgically removed human glioblastoma sections as demonstrated by in vitro phosphor imager studies. These findings suggest [(18)F]1 may be a promising radiotracer for imaging VEGFR2 in brain using PET.
Asunto(s)
Ligandos , Quinazolinas/síntesis química , Radiofármacos/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/química , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos , Radioisótopos de Flúor/química , Glioma/diagnóstico , Glioma/metabolismo , Glioma/patología , Humanos , Tomografía de Emisión de Positrones , Quinazolinas/química , Radiofármacos/química , Estereoisomerismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
The in vivo dynamic behavior of ginkgolide B (GB), a terpene lactone constituent of the Ginkgo biloba extracts, in the living animal was visualized by positron emission tomographic (PET) imaging using a GB analogue labeled with the positron emitter (18)F. The in vivo imaging studies, combined with ex vivo dissection experiments, reveal that GB exists in 2 forms in the body: the original GB with its lactone rings closed and a second form with one of the rings open. The original GB in plasma is taken up rapidly by various organs including the liver, the intestine and possibly the stomach. Consequently, in plasma, the proportion of the ionized form of GB increases dramatically with time. Thereafter the ratio between the 2 forms appears to shift slowly towards equilibrium. The results suggest that more attention needs to be focused on in vivo dynamics between the 2 forms of GB.