Substitution of the Lys linker with the β-Ala linker dramatically decreased the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone peptides.

Abstract

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg(11))CCMSH (2), RVD-β-Ala-(Arg(11))CCMSH (3), RAD-β-Ala-(Arg(11))CCMSH (4), NAD-β-Ala-(Arg(11))CCMSH (5), and EAD-β-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 (99m)Tc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six (99m)Tc-peptides. (99m)Tc-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 (99m)Tc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using (99m)Tc-4 as an imaging probe.

• Authors: Adam M Flook, Jianquan Yang, Yubin Miao
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 21 Pg. 9010-8 (Nov 13 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 25290883 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dipeptides
• Organotechnetium Compounds
• Receptor, Melanocortin, Type 1
• beta-Alanine
• alanylaspartic acid
• alpha-MSH
• Lysine

Topics

• Animals
• Dipeptides
• Female
• Kidney (metabolism)
• Liver (metabolism)
• Lysine (metabolism)
• Melanoma, Experimental (diagnostic imaging)
• Mice, Inbred C57BL
• Organotechnetium Compounds
• Receptor, Melanocortin, Type 1 (metabolism)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon
• alpha-MSH (analogs & derivatives)
• beta-Alanine (metabolism)