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

Sweety Mittal; Rohit Sharma; Madhava B Mallia; Haladhar Dev Sarma

doi:10.1016/j.nucmedbio.2021.03.004

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

Nucl Med Biol. 2021 May-Jun:96-97:61-67. doi: 10.1016/j.nucmedbio.2021.03.004. Epub 2021 Mar 26.

Authors

Sweety Mittal¹, Rohit Sharma², Madhava B Mallia³, Haladhar Dev Sarma⁴

Affiliations

¹ Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085, India. Electronic address: sweetys@barc.gov.in.
² Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085, India. Electronic address: rohitshr@barc.gov.in.
³ Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India. Electronic address: mallia@barc.gov.in.
⁴ Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India. Electronic address: hdsarma@barc.gov.in.

PMID: 33838524
DOI: 10.1016/j.nucmedbio.2021.03.004

Abstract

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 ⁶⁸Ga-labeled radiotracers, [⁶⁸Ga]Ga-DOTAGA-2-NIM and [⁶⁸Ga]Ga-NODAGA-2-NIM, for hypoxia targeting applications.

Methods: Bifunctional chelating agents suitable for radiolabeling with ⁶⁸Ga, 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 [⁶⁸Ga]GaCl₃ obtained from a commercial ⁶⁸Ge/⁶⁸Ga-generator to obtain corresponding ⁶⁸Ga-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 ⁶⁸Ga complexes of 2-NIM-DOTAGA and 2-NIM-NODAGA could be prepared in ~82% and ~90% yield, respectively. In vitro studies of the complexes in CHO cells showed significant accumulation of [⁶⁸Ga]Ga-NODAGA-2-NIM complex under hypoxic conditions with hypoxic to normoxic ratio of 2.88 ± 0.36 at 180 min post incubation. The [⁶⁸Ga]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. [⁶⁸Ga]Ga-NODAGA-2-NIM showed a more favorable pharmacokinetics with respect to [⁶⁸Ga]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.

Keywords: BFCA; Bifunctional chelating agent; Gallium-68; Nitroimidazole; Positron emission tomography; Tumor hypoxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetates
Animals
Cell Line, Tumor
Gallium Radioisotopes
Heterocyclic Compounds, 1-Ring
Mice
Positron-Emission Tomography*
Tissue Distribution
Tumor Hypoxia

Substances

1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
Acetates
Gallium Radioisotopes
Heterocyclic Compounds, 1-Ring