Structural Modification on the Lys Linker Enhanced Tumor to Kidney Uptake Ratios of 99mTc-Labeled RGD-Conjugated α-MSH Hybrid Peptides

The purpose of this study was to examine whether the structural modification on the positively charged Lys linker could reduce the kidney uptake of (99m)Tc-labeled Arg-Gly-Asp (RGD)-conjugated α-melanocyte stimulating hormone (α-MSH) hybrid peptides. The RGD motif {cyclic(Arg-Gly-Asp-D-Tyr-Asp)} was coupled to [Cys(3,4,10), D-Phe(7), Arg(11)]α-MSH(3-13) {(Arg(11))CCMSH} through a neutral glycine linker to eliminate the positively charged amino side chain of the Lys linker or without a linker to delete the Lys linker. The receptor binding affinity of RGD-Gly-(Arg(11))CCMSH and RGD-(Arg(11))CCMSH was determined in B16/F1 melanoma cells. The melanoma targeting and imaging properties of (99m)Tc-RGD-Gly-(Arg(11))CCMSH and (99m)Tc-RGD-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The structural modification on the Lys linker retained a low nanomolar receptor binding affinity of RGD-Gly-(Arg(11))CCMSH and RGD-(Arg(11))CCMSH (1.5 and 1.0 nM, respectively). The structural modification on the Lys linker dramatically decreased the renal uptake of (99m)Tc-RGD-Gly-(Arg(11))CCMSH and (99m)Tc-RGD-(Arg(11))CCMSH by 79% and 77% at 4 h postinjection compared to (99m)Tc-RGD-Lys-(Arg(11))CCMSH. (99m)Tc-RGD-(Arg(11))CCMSH displayed a higher melanoma uptake (16.12 ± 3.09% ID/g) than (99m)Tc-RGD-Gly-(Arg(11))CCMSH (11.50 ± 1.01% ID/g) at 2 postinjection. The tumor uptake of (99m)Tc-RGD-(Arg(11))CCMSH was 1.4 times the tumor uptake of (99m)Tc-RGD-Gly-(Arg(11))CCMSH at 2 postinjection. A dramatically enhanced tumor-to-kidney uptake ratio of (99m)Tc-RGD-(Arg(11))CCMSH suggests that (188)Re-RGD-(Arg(11))CCMSH may behave in a similar fashion warranting future evaluation for melanoma treatment.