68Ga-labeled PET tracers for targeting tumor hypoxia: Role of bifunctional chelators on pharmacokinetics

Introduction: By virtue of their oxygen dependant accumulation in hypoxic cells, radiolabeled nitroimidazole analogues have been widely used for detecting tumor hypoxia. Present study evaluates two 2-nitroimidazole (2-NIM) based Ga-68-labeled radiotracers, [Ga-68]Ga-DOTAGA-2-NIM and [Ga-68]Ga-NODAGA-2-NIM, for hypoxia targeting applications. Methods: Bifunctional chelating agents suitable for radiolabeling with Ga-68, viz. 1,4,7,10-tetraazacyclododececane,1-(glutaric acid)-4,7,10-triacetic acid (DOTAGA) and 1,4,7-triazacyclododececane,1-(glutaric acid)-4,7-diacetic acid (NODAGA), were coupled to appropriately modified 2-nitroimidazole to obtain 2-NIM-DOTAGA and 2-NIM-NODAGA, respectively. These ligands were radiolabeled using [Ga-68]GaCl3 obtained from a commercial Ge-68/Ga-68-generator to obtain corresponding Ga-68-complexes. Both the radiotracers were tested for their hypoxia selectivity in CHO cells under hypoxic and normoxic conditions. Biodistribution studies in fibrosarcoma tumor bearing Swiss mice were carried out to evaluate the radiotracer in vivo. Results: The Ga-68 complexes of 2-NIM-DOTAGA and 2-NIM-NODAGA could be prepared in similar to 82% and similar to 90% yield, respectively. In vitro studies of the complexes in CHO cells showed significant accumulation of [Ga-68]Ga-NODAGA-2NIM complex under hypoxic conditions with hypoxic to normoxic ratio of 2.88 +/- 0.36 at 180 min post incubation. The [Ga-68]Ga-DOTAGA-2-NIM complex also showed hypoxia selectivity albeit to a lesser extent. Biodistribution studies of the complexes in Swiss mice bearing fibrosarcoma tumor showed significant tumor uptake by both radiolabeled complexes. [Ga-68]Ga-NODAGA-2-NIM showed a more favorable pharmacokinetics with respect to [Ga-68]Ga-DOTAGA-2-NIM. Conclusion: The nitroimidazole radiotracer with NODAGA chelator displayed more favorable pharmacokinetics and good hypoxia selectivity, making it a promising candidate for further investigation. The present study also provides an insight into the possible role of bifunctional chelator on overall pharmacokinetics of small molecule radiotracers. (C) 2021 Elsevier Inc. All rights reserved.