title: Effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-MSH peptides.
abstract: The purpose of this study was to examine the profound effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of (111)In-labeled lactam bridge-cyclized DOTA-[X]-CycMSH(hex) {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[X]-c[Asp-His-dPhe-Arg-Trp-Lys]-CONH(2); X = GGNle, GENle, or NleGE; GG = -Gly-Gly- and GE = -Gly-Glu-} peptides.
  
  
  METHODS
  Three novel peptides (DOTA-GGNle-CycMSH(hex), DOTA-GENle-CycMSH(hex), and DOTA-NleGE-CycMSH(hex)) were designed and synthesized. The melanocortin-1 (MC1) receptor-binding affinities of the peptides were determined in B16/F1 melanoma cells. The melanoma-targeting and pharmacokinetic properties of (111)In-DOTA-GGNle-CycMSH(hex) and (111)In-DOTA-GENle-CycMSH(hex) were determined in B16/F1 melanoma-bearing C57 mice.
  
  
  RESULTS
  DOTA-GGNle-CycMSH(hex) and DOTA-GENle-CycMSH(hex) displayed 2.1 and 11.5 nM MC1 receptor-binding affinities, whereas DOTA-NleGE-CycMSH(hex) showed 873.4 nM MC1 receptor-binding affinity. The introduction of the -GG- linker maintained high melanoma uptake while decreasing kidney and liver uptake of (111)In-DOTA-GGNle-CycMSH(hex). The tumor uptake of (111)In-DOTA-GGNle-CycMSH(hex) was 19.05 ± 5.04 and 18.6 ± 3.56 percentage injected dose per gram at 2 and 4 h after injection, respectively. (111)In-DOTA-GGNle-CycMSH(hex) exhibited 28%, 32%, and 42% less kidney uptake than (111)In-DOTA-Nle-CycMSH(hex) we reported previously, and 61%, 65%, and 68% less liver uptake than (111)In-DOTA-Nle-CycMSH(hex) at 2, 4, and 24 h after injection, respectively.
  
  
  CONCLUSIONS
  The amino acid linkers exhibited profound effects on the melanoma-targeting and pharmacokinetic properties of the (111)In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptides. Introduction of the -GG- linker maintained high melanoma uptake while reducing kidney and liver uptake of (111)In-DOTA-GGNle-CycMSH(hex), highlighting its potential as an effective imaging probe for melanoma detection, as well as a therapeutic peptide for melanoma treatment when labeled with a therapeutic radionuclide.
authors.affiliation: College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, USA.
authors.forename: Haixun
authors.initials: H
authors.lastname: Guo
authors.forename: Jianquan
authors.initials: J
authors.lastname: Yang
authors.forename: Fabio
authors.initials: F
authors.lastname: Gallazzi
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D003500:Cyclization; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D007202:Indicators and Reagents; D007205:Indium Radioisotopes / Q000737:chemistry* / Q000493:pharmacokinetics*; D007769:Lactams / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D008545:Melanoma / Q000000981:diagnostic imaging*; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
chemical_list: D000596:Amino Acids; D006573:Heterocyclic Compounds, 1-Ring; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D007769:Lactams; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D000521:alpha-MSH