Replacement of the Lys linker with an Arg linker resulting in improved melanoma uptake and reduced renal uptake of Tc-99m-labeled Arg-Gly-Asp-conjugated alpha-melanocyte stimulating hormone hybrid peptide.

Abstract

The purpose of this study was to reduce the non-specific renal uptake of Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone (alpha-MSH) hybrid peptide through structural modification or L-lysine co-injection. The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), D-Phe7, Arg11] alpha-MSH3-13 {(Arg11)CCMSH} through the Arg linker (substituting the Lys linker) to generate a novel RGD-Arg-(Arg11)CCMSH hybrid peptide. The melanoma targeting and pharmacokinetic properties of 99mTc-RGD-Arg-(Arg11)CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The effect of L-lysine co-injection on the renal uptake was determined through the co-injection of L-lysine with 99mTc-RGD-Arg-(Arg11)CCMSH or 99mTc-RGD-Lys-(Arg11)CCMSH. Replacement of the Lys linker with an Arg linker exhibited a profound effect in reducing the non-specific renal uptake of 99mTc-RGD-Arg-(Arg11)CCMSH, as well as increasing the tumor uptake of 99mTc-RGD-Arg-(Arg11)CCMSH compared to 99mTc-RGD-Lys-(Arg11)CCMSH. 99mTc-RGD-Arg-(Arg11)CCMSH exhibited high tumor uptake (21.41+/-3.74% ID/g at 2 h post-injection) and prolonged tumor retention (6.81+/-3.71% ID/g at 24 h post-injection) in B16/F1 melanoma-bearing mice. The renal uptake values of 99mTc-RGD-Arg-(Arg11)CCMSH were 40.14-64.08% of those of 99mTc-RGD-Lys-(Arg11)CCMSH (p<0.05) at 0.5, 2, 4 and 24 h post-injection. Co-injection of L-lysine was effective in decreasing the renal uptakes of 99mTc-RGD-Arg-(Arg11)CCMSH by 27.7% and 99mTc-RGD-Lys-(Arg11)CCMSH by 52.1% at 2 h post-injection. Substitution of the Lys linker with an Arg linker dramatically improved the melanoma uptake and reduced the renal uptake of 99mTc-RGD-Arg-(Arg11)CCMSH, warranting the further evaluation of 188Re-labeled RGD-Arg-(Arg11)CCMSH as a novel MC1 receptor-targeting therapeutic peptide for melanoma treatment in the future.

• Authors: Jianquan Yang, Haixun Guo, R Steve Padilla, Marianne Berwick, Yubin Miao
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 18 Issue 18 Pg. 6695-700 (Sep 15 2010) ISSN: 1464-3391 [Electronic] England
• PMID: 20728365 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Oligopeptides
• Organoplatinum Compounds
• alpha-MSH
• Technetium
• arginyl-glycyl-aspartic acid
• Melanocyte-Stimulating Hormones
• Arginine
• Lysine

Topics

• Amino Acid Sequence
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacokinetics)
• Arginine (chemistry)
• Isotope Labeling
• Kidney (metabolism)
• Lysine (chemistry)
• Melanocyte-Stimulating Hormones (chemical synthesis, chemistry, pharmacokinetics)
• Melanoma, Experimental (metabolism)
• Mice
• Mice, Inbred C57BL
• Oligopeptides (chemistry)
• Organoplatinum Compounds (chemical synthesis, chemistry, pharmacokinetics)
• Technetium (chemistry)
• Whole Body Imaging
• alpha-MSH (chemistry)