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PET imaging of tumor hypoxia using 18F-labeled pimonidazole. | LitMetric

AI Article Synopsis

Article Abstract

Background: Tumor hypoxia contributes to loco-regional failure, and for optimal treatment planning, knowledge about tumor hypoxia in individual patients is required. Nitroimidazole-based tracers, which are retained in hypoxic cells, allow PET-based assessment of tumor hypoxia, but current tracers are characterized by slow tracer retention and clearance, resulting in low inter-tissue contrast. Pimonidazole is an immune detectable hypoxia marker widely used for detection of hypoxia in tumor samples. Pimonidazole has excellent chemical properties for hypoxia imaging, but labeling for non- invasive assay has not been attempted. Here we labeled pimonidazole with (18)F ([(18)F]FPIMO).

Material And Methods: [(18)F]FPIMO was produced by fluorination of 1-[2-O-tosyl-3-(2-nitroimidazole-1-yl)-propyl]-piperidine, which resulted in two isomeric interchangeable forms (named "5" and "6") with a radiochemical purity of 91-100%. [(18)F]FPIMO was tested by incubation of two different tumor cell lines at high and low oxygen levels. [(18)F]FPIMO was also administered to tumor-bearing mice and tracer retention in tumors, non-hypoxic reference tissues and tissues involved in drug metabolism/clearance was evaluated by various techniques.

Results And Conclusions: Retention of [(18)F]FPIMO was strongly hypoxia-driven in vitro, but isomeric form "5" was particularly promising and reached impressive anoxic-to-oxic retention ratios of 36 and 102, in FaDuDD and SiHa cells, respectively, following three hours of tracer incubation. This was equal to or higher than ratios measured using the established hypoxia tracer [(18)F]FAZA. [(18)F]FPIMO also accumulated in tumors grown in mice, and reached tumor levels that were two to six-fold higher than in muscle three hours post-administration. Furthermore, the intra-tumoral distribution of [(18)F]FPIMO (autoradiography) and unlabeled pimonidazole (immunohistochemistry) was largely identical. Nonetheless, [(18)F]FPIMO proved inferior to [(18)F]FAZA, since absolute tumor signal and intra-tumoral contrast was low, thus compromising PET imaging. Low tumor signal was coupled to extensive tracer accumulation in liver and kidneys, and analysis of blood metabolites revealed that [(18)F]FPIMO was metabolized rapidly, with little parent compound remaining 15 minutes post-administration. Ongoing work focuses on the possibility of labeling pimonidazole in different positions with (18)F to improve tracer stability in vivo.

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http://dx.doi.org/10.3109/0284186X.2013.815797DOI Listing

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