Investigation of the Effect on the Albumin Binding Moiety for the Pharmacokinetic Properties of 68Ga-, 205/206Bi-, and 177Lu-Labeled NAPamide-Based Radiopharmaceuticals

Dániel Szücs; Judit P Szabó; Viktória Arató; Barbara Gyuricza; Dezső Szikra; Imre Tóth; Zita Képes; György Trencsényi; Anikó Fekete

doi:10.3390/ph16091280

Investigation of the Effect on the Albumin Binding Moiety for the Pharmacokinetic Properties of ⁶⁸Ga-, ^205/206Bi-, and ¹⁷⁷Lu-Labeled NAPamide-Based Radiopharmaceuticals

Pharmaceuticals (Basel). 2023 Sep 11;16(9):1280. doi: 10.3390/ph16091280.

Authors

Dániel Szücs^{1

2

3}, Judit P Szabó^{1

4}, Viktória Arató^{1

5}, Barbara Gyuricza¹, Dezső Szikra¹, Imre Tóth², Zita Képes¹, György Trencsényi¹, 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.

Abstract

Although radiolabeled alpha-melanocyte stimulating hormone-analogue NAPamide derivatives are valuable melanoma-specific diagnostic probes, their rapid elimination kinetics and high renal uptake may preclude them from being used in clinical settings. We aimed at improving the pharmacokinetics of radiolabeled DOTA-NAPamide compounds by incorporating a 4-(p-iodo-phenyl)-butanoic acid (IPB) into the molecules. Followed by ⁶⁸Ga-, ^205/206Bi-, and ¹⁷⁷Lu-labelling, the radiopharmaceuticals ([⁶⁸Ga]Ga-DOTA-IPB-NAPamide, [^205/206Bi]Bi-DOTA-IPB-NAPamide, [¹⁷⁷Lu]Lu-DOTA-IPB-NAPamide) were characterized in vitro. To test the imaging behavior of the IPB-containing probes, B16F10 tumor-bearing C57BL/6 mice were subjected to in vivo microPET/microSPECT/CT imaging and ex vivo biodistribution studies. All tracers were stable in vitro, with radiochemical purity exceeding 98%. The use of albumin-binding moiety lengthened the in vivo biological half-life of the IPB-carrying radiopharmaceuticals, resulting in elevated tumor accumulation. Both [⁶⁸Ga]Ga-DOTA-IPB-NAPamide (5.06 ± 1.08 %ID/g) and [^205/206Bi]Bi-DOTA-IPB-NAPamide (4.50 ± 0.98 %ID/g) exhibited higher B16F10 tumor concentrations than their matches without the albumin-binding residue ([⁶⁸Ga]Ga-DOTA-NAPamide and [^205/206Bi]Bi-DOTA-NAPamide: 1.18 ± 0.27 %ID/g and 3.14 ± 0.32; respectively), however; the large amounts of off-target radioactivity do not confirm the benefits of half-life extension for short-lived isotopes. Enhanced [¹⁷⁷Lu]Lu-DOTA-IPB-NAPamide tumor uptake even 24 h post-injection proved the advantage of IPB-based prolonged circulation time regarding long-lived radionuclides, although the significant background noise must be addressed in this case as well.

Keywords: NAPamide; albumin-binding moiety; malignant melanoma (MM); melanocortin-1 receptor (MC1-R); positron emission tomography (PET); radiolabeling; single-photon emission computed tomography/computed tomography (SPECT/CT).

Grants and funding

This research received no external funding.