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

Copyright © 2021 Elsevier Inc. All rights reserved..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:96-97

Enthalten in:

Nuclear medicine and biology - 96-97(2021) vom: 15. Mai, Seite 61-67

Sprache:

Englisch

Beteiligte Personen:

Mittal, Sweety [VerfasserIn]
Sharma, Rohit [VerfasserIn]
Mallia, Madhava B [VerfasserIn]
Sarma, Haladhar Dev [VerfasserIn]

Links:

Volltext

Themen:

1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane
Acetates
BFCA
Bifunctional chelating agent
Gallium Radioisotopes
Gallium-68
Heterocyclic Compounds, 1-Ring
Journal Article
Nitroimidazole
Positron emission tomography
Research Support, Non-U.S. Gov't
Tumor hypoxia

Anmerkungen:

Date Completed 16.12.2021

Date Revised 16.12.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.nucmedbio.2021.03.004

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM323936024