¹¹¹In-labeled lactam bridge-cyclized α-melanocyte stimulating hormone peptide analogues for melanoma imaging

The purpose of this study was to examine the influence of the lactam bridge cyclization on melanoma targeting and biodistribution properties of the radiolabeled conjugates. Two novel lactam bridge-cyclized α-MSH peptide analogues, DOTA-CycMSH (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]) and DOTA-GlyGlu-CycMSH (DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]), were synthesized and radiolabeled with ¹¹¹In. The internalization and efflux of ¹¹¹In-labeled CycMSH peptides were examined in B16/F1 melanoma cells. The melanoma targeting properties, pharmacokinetics, and SPECT/CT imaging of ¹¹¹In-labeled CycMSH peptides were determined in B16/F1 melanoma-bearing C57 mice. Both ¹¹¹In-DOTA-CycMSH and ¹¹¹In-DOTA-GlyGlu-CycMSH exhibited fast internalization and extended retention in B16/F1 cells. The tumor uptake values of ¹¹¹In-DOTA- CycMSH and ¹¹¹In-DOTA-GlyGlu-CycMSH were 9.53 ± 1.41% injected dose/gram (% ID/g) and 10.40 ± 1.40% ID/g at 2 h postinjection, respectively. Flank melanoma tumors were clearly visualized with ¹¹¹In-DOTA-CycMSH and ¹¹¹In-DOTA-GlyGlu-CycMSH by SPECT/CT images at 2 h postinjection. Whole-body clearance of the peptides was fast, with greater than 90% of the radioactivities cleared through urinary system by 2 h postinjection. There was low radioactivity (<0.8% ID/g) accumulated in blood and normal organs except kidneys at all time points investigated. Introduction of a negatively charged linker (-Gly-Glu-) into the peptide sequence decreased the renal uptake by 44% without affecting the tumor uptake at 4 h postinjection. High receptor-mediated melanoma uptakes coupled with fast whole-body clearance in B16ZF1 melanoma-bearing C57 mice demonstrated the feasibility of using ¹¹¹In-labeled lactam bridge-cyclized α-MSH peptide analogues as a novel class of imaging probes for receptor-targeting melanoma imaging.