Substitution of the Lys Linker with the beta-Ala Linker Dramatically Decreased the Renal Uptake of Tc-99m-Labeled Arg-X-Asp-Conjugated and X-Ala-Asp-Conjugated alpha-Melanocyte Stimulating Hormone Peptides

作者：Flook Adam M; Yang Jianquan; Miao Yubin^*

来源：Journal of Medicinal Chemistry, 2014, 57(21): 9010-9018.

DOI：10.1021/jm501114v

The purpose of this study was to examine whether the substitution of the Lys linker with the beta-Ala could reduce the renal uptake of Tc-99m-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated a-melanocyte stimulating hormone (alpha-MSH) peptides. RSD-beta-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-beta-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-beta-Ala-(Arg(11))CCMSH (2), RVD-beta-Ala-(Arg(11))CCMSH (3), RAD-beta-Ala-(Arg(11))CCMSH (4), NAD-beta-Ala-(Arg(11))CCMSH (5), and EAD-beta-Ala-(Arg(11))CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their Tc-99m-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with B-Ala linker dramatically reduced the renal uptake of all six Tc-99m-peptides. Tc-99m-4 exhibited the highest melanoma uptake (15.66 +/- 6.19% ID/g) and the lowest kidney uptake (20.18 +/- 3.86% ID/g) among these Tc-99m-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using Tc-99m-4 as an imaging probe.

• 出版日期2014-11-13