title: Radiopharmacological characterization of ⁶⁴Cu-labeled α-MSH analogs for potential use in imaging of malignant melanoma.
abstract: The melanocortin-1 receptor (MC1R) plays an important role in melanoma growth, angiogenesis and metastasis, and is overexpressed in melanoma cells. α-Melanocyte stimulating hormone (α-MSH) and derivatives are known to bind with high affinity at this receptor that provides the potential for selective targeting of melanoma. In this study, one linear α-MSH-derived peptide Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH2 (NAP-NS1) without linker and with εAhx-β-Ala linker, and a cyclic α-MSH derivative, [Lys-Glu-His-D-Phe-Arg-Trp-Glu]-Arg-Pro-Val-NH2 (NAP-NS2) with εAhx-β-Ala linker were conjugated with p-SCN-Bn-NOTA and labeled with (64)Cu. Radiochemical and radiopharmacological investigations were performed with regard to transchelation, stability, lipophilicity and in vitro binding assays as well as biodistribution in healthy rats. No transchelation reactions, but high metabolic stability and water solubility were demonstrated. The linear derivatives showed higher affinity than the cyclic one. [(64)Cu]Cu-NOTA-εAhx-β-Ala-NAP-NS1 ([(64)Cu]Cu-2) displayed rapid cellular association and dissociation in murine B16F10 cell homogenate. All [(64)Cu]Cu-labeled conjugates exhibited affinities in the low nanomolar range in B16F10. [(64)Cu]Cu-2 showed also high affinity in human MeWo and TXM13 cell homogenate. In vivo studies suggested that [(64)Cu]Cu-2 was stable, with about 85 % of intact peptide in rat plasma at 2 h p.i. Biodistribution confirmed the renal pathway as the major elimination route. The uptake of [(64)Cu]Cu-2 in the kidney was 5.9 % ID/g at 5 min p.i. and decreased to 2.0 % ID/g at 60 min p.i. Due to the prospective radiochemical and radiopharmacological properties of the linear α-MSH derivative [(64)Cu]Cu-2, this conjugate is a promising candidate for tracer development in human melanoma imaging.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.|Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany. w.sihver@hzdr.de.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Sihver
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.|Brandenburg University of Technology Cottbus-Senftenberg, Cottbus, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jurischka
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Haase-Kohn
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Mosch
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.|Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: Department of Pharmacological and Pharmaceutical Sciences, University of Padua, 35131, Padua, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Carta
authors.affiliation: IENI-CNR, Corso Stati Uniti, 35127, Padua, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bolzati
authors.affiliation: ICB-CNR, 35131, Padua, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calderan
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.|Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328, Dresden, Germany.|Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062, Dresden, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Pietzsch
mesh_terms: D000818:Animals; D003301:Copper Radioisotopes / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D003952:Diagnostic Imaging / Q000295:instrumentation*; D004355:Drug Stability; D006801:Humans; D008297:Male; D008545:Melanoma / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012878:Skin Neoplasms; D014018:Tissue Distribution; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000096142:Cutaneous Malignant Melanoma
chemical_list: D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; D000521:alpha-MSH
keywords: 64Cu labeling; Malignant melanoma; Melanocortin-1 receptor; α-MSH analogs