Synthesis, Physicochemical, Labeling and In Vivo Characterization of 44Sc-Labeled DO3AM-NI as a Hypoxia-Sensitive PET Probe

Dániel Szücs; Tibor Csupász; Judit P Szabó; Adrienn Kis; Barbara Gyuricza; Viktória Arató; Viktória Forgács; Adrienn Vágner; Gábor Nagy; Ildikó Garai; Dezső Szikra; Imre Tóth; György Trencsényi; Gyula Tircsó; Anikó Fekete

doi:10.3390/ph15060666

Synthesis, Physicochemical, Labeling and In Vivo Characterization of ⁴⁴Sc-Labeled DO3AM-NI as a Hypoxia-Sensitive PET Probe

Pharmaceuticals (Basel). 2022 May 26;15(6):666. doi: 10.3390/ph15060666.

Authors

Dániel Szücs^{1

2

3}, Tibor Csupász^{2

3}, Judit P Szabó^{1

4}, Adrienn Kis¹, Barbara Gyuricza^{1

3}, Viktória Arató^{1

5}, Viktória Forgács^{1

3}, Adrienn Vágner⁶, Gábor Nagy⁶, Ildikó Garai^{1

6}, Dezső Szikra^{1

6}, Imre Tóth², György Trencsényi^{1

6}, Gyula Tircsó², Anikó Fekete¹

Affiliations

¹ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98., H-4032 Debrecen, Hungary.
² Department of Physical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem tér 1., H-4032 Debrecen, Hungary.
³ Doctoral School of Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem tér 1., H-4032 Debrecen, Hungary.
⁴ Doctoral School of Clinical Medicine, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98., H-4032 Debrecen, Hungary.
⁵ Doctoral School of Pharmaceutical Sciences, Faculty of Pharmacy, University of Debrecen, Nagyerdei krt. 98., H-4032 Debrecen, Hungary.
⁶ Scanomed Ltd., Nagyerdei krt. 98., H-4032 Debrecen, Hungary.

Abstract

Hypoxia promotes angiogenesis, which is crucial for tumor growth, and induces malignant progression and increases the therapeutic resistance. Positron emission tomography (PET) enables the detection of the hypoxic regions in tumors using 2-nitroimidazole-based radiopharmaceuticals. We describe here a physicochemical study of the Sc(DO3AM-NI) complex, which indicates: (a) relatively slow formation of the Sc(DO3AM-NI) chelate in acidic solution; (b) lower thermodynamic stability than the reference Sc(DOTA); (c) however, it is substantially more inert and consequently can be regarded as an excellent Sc-binder system. In addition, we report a comparison of ⁴⁴Sc-labeled DO3AM-NI with its known ⁶⁸Ga-labeled analog as a hypoxia PET probe. The in vivo and ex vivo biodistributions of ⁴⁴Sc- and ⁶⁸Ga-labeled DO3AM-NI in healthy and KB tumor-bearing SCID mice were examined 90 and 240 min after intravenous injection. No significant difference was found between the accumulation of ⁴⁴Sc- and ⁶⁸Ga-labeled DO3AM-NI in KB tumors. However, a significantly higher accumulation of [⁶⁸Ga]Ga(DO3AM-NI) was found in liver, spleen, kidney, intestine, lung, heart and brain than for [⁴⁴Sc]Sc(DO3AM-NI), leading to a lower tumor/background ratio. The tumor-to-muscle (T/M) ratio of [⁴⁴Sc]Sc(DO3AM-NI) was approximately 10-15-fold higher than that of [⁶⁸Ga]Ga(DO3AM-NI) at all time points. Thus, [⁴⁴Sc]Sc(DO3AM-NI) allows the visualization of KB tumors with higher resolution, making it a promising hypoxia-specific PET radiotracer.

Keywords: physicochemical study; positron emission tomography; radiochemistry; radiopharmaceutical; scandium-44; tumor hypoxia.

Abstract

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