PET imaging of tumor hypoxia using 18F-labeled pimonidazole. (October 2013)

• Record Type: Journal Article
• Authors: Busk, Morten; Jakobsen, Steen; Horsman, Michael R.; Mortensen, Lise S.; Iversen, Ane B.; Overgaard, Jens; Nordsmark, Marianne; Ji, Xiaosheng; Lee, David Y.; Raleigh, James R.
• Is Part Of: Acta oncologica. Volume 52:Number 7(2013)
• Page Start: 1300
• Page End: 1307
• Publication Date: 2013-10
• Subjects: Oncology -- Periodicals; Cancer -- Treatment -- Periodicals; 616.992
• DOI: 10.3109/0284186X.2013.815797
• Languages: English
• ISSNs: 0284-186X

Abstract

<abstract> <title>Abstract</title> <p> <italic>Background.</italic> 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 <sup>18</sup>F ([<sup>18</sup>F]FPIMO). <italic>Material and methods.</italic> [<sup>18</sup>F]FPIMO was produced by fluorination of 1-[2-<italic>O</italic>-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%. [<sup>18</sup>F]FPIMO was tested by incubation of two different tumor cell lines at high and low oxygen levels. [<sup>18</sup>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. <italic>Results and conclusions.</italic> Retention of [<sup>18</sup>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 FaDu<sub>DD</sub> and SiHa cells, respectively, following three hours of tracer incubation. This was equal to or higher than ratios measured using the established hypoxia tracer [<sup>18</sup>F]FAZA. [<sup>18</sup>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 [<sup>18</sup>F]FPIMO (autoradiography) and unlabeled pimonidazole (immunohistochemistry) was largely identical. Nonetheless, [<sup>18</sup>F]FPIMO proved inferior to [<sup>18</sup>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 [<sup>18</sup>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 <sup>18</sup>F to improve tracer stability in vivo.</p> </abstract>