Dual receptor-targeting 99mTc-labeled Arg-Gly-Asp-conjugated Alpha-Melanocyte stimulating hormone hybrid peptides for human melanoma imaging

Introduction: The aim of this study was to examine whether the substitution of the Lys linker with the aminooctanoic acid (Aoc) and polyethylene glycol (PEG) linker could substantially decrease the non-specific renal uptake of Tc-99m-labeled Arg-Gly-Asp-conjugated alpha-melanocyte stimulating hormone (alpha-MSH) hybrid peptides. Methods: The RGD motif {Arg-Gly-Asp-DTyr-Asp} was coupled to [Cys(3,4,10), D-Phe(7), Arg(11)]alpha-MSH3-13 via the Aoc or PEG(2) linker to generate RGD-Aoc-(Arg(11))CCMSH and RGD-PEG-(Arg(11))CCMSH. The biodistribution results of Tc-99m-RGD-Aoc-(Arg(11))CCMSH and Tc-99m-RGD-PEG(2)-(Arg(11))CCMSH were examined in M21 human melanomaxenografted nude mice. Results: The substitution of Lys linker with Aoc and PEG(2) linker significantly reduced the renal uptake of Tc-99m-RGDAoc-(Arg(11))CCMSH and Tc-99m-RGD-PEG(2)-(Arg(11))CCMSH by 58% and 63% at 2 h post-injection. The renal uptake of Tc-99m-RGD-Aoc-(Arg(11))CCMSH and Tc-99m-RGD-PEG(2)-(Arg(11))CCMSH was 27.93 +/- 3.98 and 22.01 +/- 9.89% ID/g at 2 h post-injection. Tc-99m-RGD-Aoc-(Arg(11))CCMSH displayed higher tumor uptake than Tc-99m-RGD-PEG(2)-(Arg(11)) CCMSH (235 +/- 0.12 vs. 1.71 +/- 0.25% ID/g at 2 h post-injection). The M21 human melanoma lesions could be clearly visualized by SPECT/CT using Tc-99m-RGD-Aoc-(Arg(11))CCMSH as an imaging probe. Conclusions: The favorable effect of Aoc and PEG(2) linker in reducing the renal uptake provided a new insight into the design of novel dual receptor-targeting radiolabeled peptides. (C) 2014 Elsevier Inc. All rights reserved.