Development of 68Ga-Labeled Multivalent Nitroimidazole Derivatives for Hypoxia Imaging

Abstract

Abstract Development of 68Ga-Labeled Multivalent Nitroimidazole Derivatives for Hypoxia Imaging Seelam Sudhakara Reddy Department of Nuclear Medicine Interdisciplinary Program in Radiation Applied Life Science The Graduate School Seoul National University College of Medicine

Radiolabeled nitroimidazole (NI) derivatives have been extensively studied for imaging hypoxia. To increase the hypoxic tissue uptake, we developed 68Ga-labeled agents based on mono-, bis-, and trisnitroimidazole conjugates with the chelating agent 1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid] (TRAP). All the three agents showed high radiolabeling yields (>96%) and were found to be stable up to 4 h in prepared medium at room temperature and in human serum at 37 °C. The trivalent agent showed a significant increase in hypoxic to normoxic uptake ratio (p < 0.005) according to the in vitro cell uptake experiments. Immunohistochemical analysis confirmed the presence of hypoxia in xenografted CT26 tumor tissue. The trivalent derivative (68Ga-3: 0.17 ± 0.04, 68Ga-4: 0.33 ± 0.04, 68Ga-5: 0.45 ± 0.09, and 68Ga-6: 0.47 ± 0.05% ID/g) showed the highest uptake by tumor cells according to the biodistribution studies in CT-26 xenografted mice. All the nitroimidazole derivatives showed significantly higher uptake by tumor cells than the control agent (p < 0.05) at 1 h post-injection. The trivalent derivative (68Ga-3: 0.10 ± 0.06

68Ga-4: 0.20 ± 0.06

68Ga-5: 0.33 ± 0.08

68Ga-6: 0.59 ± 0.09) also showed the highest standard uptake value for tumor cells at 1 h post-injection in animal PET studies using CT-26 xenografted mice. In conclusion, we successfully synthesized multivalent 68Ga-labeled NI derivatives for imaging hypoxia. Among them, the trivalent agent showed the highest tumor uptake in biodistribution and animal PET studies. Keywords: trisnitroimidazole

bisnitroimidazole

multidentate

gallium-68

hypoxia

PET.

Student number: 2010-31372