In Vivo evaluation of newly synthesized 213Bi-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptide analogues in melanocortin-1 receptor (MC1-R) positive experimental melanoma model

Ibolya Kálmán-Szabó; Zita Képes; Anikó Fekete; Adrienn Vágner; Gábor Nagy; Dániel Szücs; Barbara Gyuricza; Viktória Arató; József Varga; Levente Kárpáti; Ildikó Garai; István Mándity; Frank Bruchertseifer; János Elek; Dezs Szikra; György Trencsényi

doi:10.1016/j.jpba.2023.115374

In Vivo evaluation of newly synthesized ²¹³Bi-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptide analogues in melanocortin-1 receptor (MC1-R) positive experimental melanoma model

J Pharm Biomed Anal. 2023 May 30:229:115374. doi: 10.1016/j.jpba.2023.115374. Epub 2023 Mar 28.

Authors

Ibolya Kálmán-Szabó¹, Zita Képes², Anikó Fekete³, Adrienn Vágner⁴, Gábor Nagy⁴, Dániel Szücs⁵, Barbara Gyuricza⁶, Viktória Arató⁷, József Varga³, Levente Kárpáti⁸, Ildikó Garai⁹, István Mándity¹⁰, Frank Bruchertseifer¹¹, János Elek¹², Dezs Szikra³, György Trencsényi¹

Affiliations

¹ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Gyula Petrányi Doctoral School of Clinical Immunology and Allergology, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
² Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary. Electronic address: kepes.zita@med.unideb.hu.
³ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
⁴ Scanomed Ltd., Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
⁵ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Department of Physical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem square 1, H-4032 Debrecen, Hungary; Doctoral School of Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem square 1, H-4032 Debrecen, Hungary.
⁶ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Doctoral School of Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem square 1, H-4032 Debrecen, Hungary.
⁷ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Doctoral School of Pharmaceutical Sciences, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
⁸ Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre St. 7, H-1092 Budapest, Hungary.
⁹ Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Scanomed Ltd., Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary.
¹⁰ Department of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre St. 7, H-1092 Budapest, Hungary; Artificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok boulevard 2, H-1117 Budapest, Hungary.
¹¹ European Commission, Joint Research Centre (JRC), Karlsruhe, Germany.
¹² Department of Inorganic and Analytical Chemistry, University of Debrecen, Nagyerdei St. 98, H-4032 Debrecen, Hungary; Science Port Ltd., Debrecen, Elek St. 166, H-4225 Debrecen, Hungary.

PMID: 37001274
DOI: 10.1016/j.jpba.2023.115374

Abstract

Given the rising pervasiveness of melanocortin-1 receptor (MC1-R) positive melanoma malignum (MM) and pertinent metastases, radiolabelled receptor-affine alpha-melanocyte stimulating hormone-analogue (α-MSH analogue) imaging probes would be of crucial importance in timely tumor diagnostic assessment. Herein we aimed at investigating the biodistribution and the MM targeting potential of newly synthesized ²¹³Bi-conjugated MC1-R specific peptide-based radioligands with the establishment of MC1-R overexpressing MM preclinical model. DOTA-conjugated NAP, -HOLD, -FOLD, -and MARSamide were labelled with ²¹³Bi. Ex vivo biodistribution studies were conducted post-administration of 3.81 ± 0.32 MBq [²¹³Bi]Bi-DOTA conjugated deriva-tives into twenty B16-F10 tumor-bearing C57BL/6 J and healthy mice. Organ Level Internal Dose Assessment (OLINDA) and IDAC-Dose were used to calculate translational data-based absorbed radiation dose in human organs. Moderate or low %ID/g uptake of [²¹³Bi]Bi-DOTA conjugated NAP, -HOLD, -and MARSamide and significantly increased [²¹³Bi]Bi-DOTA-FOLDamide accumulation was observed in the thoracic and abdominal organs (p ≤ 0.01). High [²¹³Bi]Bi-DOTA-NAP (%ID/g:3.76 ± 0.96), -and FOLDamide (%ID/g:3.28 ± 0.95) tumor tracer activity confirmed their MC1-R-affinity. The bladder wall received the highest radiation absorbed dose followed by the kidneys (bladder wall: 1.95·10^-2 and 8.97·10^-2 mSv/MBq; kidneys: 7.47·10^-3 vs. 5.88·10^-2 mSv/MBq measured by IDAC and OLINDA; respectively) indicating the suitability of the NAPamide derivative for clinical use. These novel [²¹³Bi]Bi-DOTA-linked peptide probes displaying meaningful MC1-R affinity could be promising molecular probes in MM imaging.

Keywords: Alpha-melanocyte stimulating hormone-analogue (α-MSH analogue); Melanocortin-1 receptor (MC1-R); [(213)BiBi -DOTA-NAPamide; [(213)Bi]Bi-DOTA-FOLDamide; [(213)Bi]Bi-DOTA-HOLDamide; [(213)Bi]Bi-DOTA-MARSamide.

MeSH terms

Animals
Humans
Melanocyte-Stimulating Hormones
Melanoma, Experimental* / diagnostic imaging
Mice
Mice, Inbred C57BL
Radiopharmaceuticals / chemistry
Receptor, Melanocortin, Type 1 / metabolism
Tissue Distribution
alpha-MSH

Substances

alpha-MSH
Receptor, Melanocortin, Type 1
Radiopharmaceuticals
Melanocyte-Stimulating Hormones