Electron-affinic compounds for labelling hypoxic cells: the synthesis and characterization of...

Highly lipophilic and protein-bound derivatives of 1-(2-phenoxy-ethyl)-2-nitroimidazole (PENI; RGW-609), a known radiosensitizer, have been prepared by introducing one (IPENI) and two (DIPENI) iodine atoms into the phenyl ring via electrophilic substitution. The electron affinity of all 3 compounds, as determined by differential pulse polarography, was similar to that for MISO, a radiosensitizer which has undergone clinical trial, but P values were 2-3 orders of magnitude greater that for MISO and %PB values were as high as 30% in vitro compared to less than 1% for MISO. 131I-PENI was prepared by catalysed halogen exchange with Na131I in greater than 90% yield, and was found to be chemically and radiochemically stable in solution for at least 2 weeks. Whole-body studies in BDF/1 mice bearing EMT-6 tumors showed rapid hepatic extraction and biliary elimination with little or no accumulation in any other tissue including tumor and fat, indicating that P and % PB values had little impact on in vivo distribution and disposition. 131I-PENI was not measurably deiodinated in vivo. IPENI and DIPENI are radiosensitizers by inference only, that is, they have not been tested for radiosensitizer properties. However, PENI, the parent compound, has been shown to be active as a radiosensitizer, and the peak potentials (polarographic) for both IPENI and DIPENI fall near those of MISO, PENI and most other 2-nitroimidazole sensitizers. The low levels of concentration in target tissues achieved by 131I-PENI mitigate against its use as a diagnostic agent.(ABSTRACT TRUNCATED AT 250 WORDS)