title: Structural modification on the Lys linker enhanced tumor to kidney uptake ratios of 99mTc-labeled RGD-conjugated α-MSH hybrid peptides.
abstract: 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.
authors.affiliation: College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, United States.
authors.forename: Jianquan
authors.initials: J
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Yubin
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000818:Animals; D005260:Female; D007668:Kidney / Q000378:metabolism; D008546:Melanoma, Experimental / Q000175:diagnosis* / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry*; D015609:Organotechnetium Compounds; D010455:Peptides / Q000737:chemistry*; D019275:Radiopharmaceuticals; D000521:alpha-MSH / Q000737:chemistry*
chemical_list: D009842:Oligopeptides; D015609:Organotechnetium Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D000521:alpha-MSH; C047981:arginyl-glycyl-aspartic acid