Síntesis y estudio de derivados de FMISO

Abstract

[18F]-FMISO is the in vivo PET (Positron Emission Tomography) radiotracer most widely used for the non-invasive assessment of hypoxic cells in tumours and ischemic areas of the brain. Tissue hypoxia plays an important role in tumour microenvironment and is well established as a resistance factor in radiotherapy. One disadvantage of using [18F]-FMISO for brain hypoxia, however, is its low permeability across the blood brain barrier (BBB). This work focused on the synthesis, radiolabelling and study of new lipophilic derivatives of FMISO bearing a lipophilic substituent such a bromo, aryl, heteroaryl or styryl group at the C-4 position on the 2-nitro-imidazole ring. The studies of toxicity, cyclic voltammetry, in vitro permeability across BBB, radiolabelling and in vitro and in vivo PET imaging studies were performed for some derivatives. The synthesized compounds were nontoxic and more easily reduced than FMISO. As expected on the basis of its computed ClogP, the phenyl derivative permeates BBB better than FMISO, but radiolabelling of this derivative has not been successful to date. Radiosynthesis of the bromo analogue was achieved, though it proved to be less efficient than the process for [18F]-FMISO. The F-18 labelled analogue performed comparably to [18F]-FMISO in the PET imaging of hypoxia in rat ischemic brain models.