Reduction of the ring size of radiolabeled lactam bridge-cyclized α-MSH peptide, resulting in enhanced melanoma uptake

The purpose of this study was to examine the profound effect of the ring size of the radiolabeled lactam bridge-cyclized α-melanocyte-stimulating hormone (α-MSH) peptide on its melanoma-targeting properties. Methods: A novel cyclic a-MSH peptide, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH₂ (DOTA-Nle-CycMSH _hex), was synthesized and radiolabeled with ¹¹¹In. The melanocortin-1 receptor-binding affinity of DOTA-Nle-CycMSH_hex was determined in B16/F1 melanoma cells. The internalization and efflux of ¹¹¹In-DOTA-Nle-CycMSH_hex were examined in B16/F1 cells. The melanoma-targeting properties and SPECT/ CT characteristics of ¹¹¹In-DOTA-Nle-CycMSH_hex were determined in B16/F1 melanoma-bearing C57 mice. Results: DOTA-Nle-CycMSH_hex displayed 1.77 nM receptor-binding affinity. ¹¹¹In-DOTA-Nle-CycMSH_hex exhibited rapid internalization and extended retention in B16/F1 cells. The tumor uptake of ¹¹¹In-DOTA-Nle-CycMSH_hex was 24.94% ± 4.58% and 10.53%6 1.11% injected dose per gram at 0.5 and 24 h after injection, respectively. Greater than 82%of the injected radioactivity was cleared through the urinary system by 2 h after injection. The tumor-to-kidney uptake ratios reached 2.04 and 1.70 at 2 and 4 h after injection, respectively. Flank melanoma tumors were clearly visualized by SPECT/CT using ¹¹¹In-DOTA-Nle-CycMSH_hex as an imaging probe at 2 and 24 h after injection. The radioactivity accumulation in normal organs, except for the kidneys, was low at 2, 4, and 24 h after injection. Conclusion: The reduction of the peptide ring size dramatically increased the melanoma uptake and decreased the renal uptake of ¹¹¹In-DOTA-Nle-CycMSH _hex, providing a new insight into the design of a novel radiolabeled lactam bridge-cyclized α-MSH peptide for melanoma imaging and treatment.