title: Tc-99m-labeled RGD-conjugated alpha-melanocyte stimulating hormone hybrid peptides with reduced renal uptake.
abstract: The purpose of this study was to examine whether the replacement of the positively-charged Lys or Arg linker with a neutral linker could reduce the renal uptake of Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (α-MSH) hybrid peptide. The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), D-Phe(7), Arg(11)]α-MSH3-13 {(Arg(11))CCMSH} through the neutral βAla or Ahx {aminohexanoic acid} linker (replacing the Lys or Arg linker) to generate novel RGD-βAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH hybrid peptides. The receptor-binding affinity and cytotoxicity of RGD-βAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH were determined in B16/F1 melanoma cells. The melanoma targeting and imaging properties of (99m)Tc-RGD-βAla-(Arg(11))CCMSH and (99m)Tc-RGD-Ahx-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The replacement of the Lys or Arg linker with the βAla or Ahx linker retained nanomolar receptor-binding affinities and remarkable cytotoxicity of RGD-βAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH. The receptor-binding affinities of RGD-βAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH were 0.8 ± 0.05 and 1.3 ± 0.1 nM. Three-hour incubation with 0.1 µM of RGD-βAla-(Arg(11))CCMSH and RGD-Ahx-(Arg(11))CCMSH decreased the survival percentages of B16/F1 cells by 71 and 67 % as compared to the untreated control cells 5 days post the treatment. The replacement of the Arg linker with the βAla or Ahx linker reduced the non-specific renal uptake of (99m)Tc-RGD-βAla-(Arg(11))CCMSH and (99m)Tc-RGD-Ahx-(Arg(11))CCMSH by 62 and 61 % at 2 h post-injection. (99m)Tc-RGD-βAla-(Arg(11))CCMSH displayed higher melanoma uptake than (99m)Tc-RGD-Ahx-(Arg(11))CCMSH at 0.5, 2, 4, and 24 h post-injection. Enhanced tumor to kidney uptake ratio of (99m)Tc-RGD-βAla-(Arg(11))CCMSH warranted the further evaluation of (188)Re-labeled RGD-βAla-(Arg(11))CCMSH as a novel MC1 receptor-targeting therapeutic peptide for melanoma treatment in the future.
authors.affiliation: College of Pharmacy, University of New Mexico, Albuquerque, NM, 87131, USA.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Yang
authors.forename: Chien-An A
authors.initials: CA
authors.lastname: Hu
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D044102:Receptor, Melanocortin, Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013667:Technetium / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution; D000521:alpha-MSH / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D009842:Oligopeptides; D019275:Radiopharmaceuticals; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH; D013667:Technetium; C047981:arginyl-glycyl-aspartic acid