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Simple Summary: There is a need to develop new theranostic approaches for malignant melanoma. Only 35% of patients with metastatic melanoma reach the milestone of 5-year survival, despite the success of new immunotherapy. We have developed a new class of peptides to target melanocortin-1 receptors (MC1Rs) that display elevated levels in human melanoma. In this study, we examined the melanoma targeting and biodistribution properties of two 67Cu-tagged peptides in tumor-bearing mice. We found that one of the peptides, namely 67Cu-NOTA-PEG2Nle-CycMSHhex, exhibited favorable melanoma targeting and biodistribution properties that underscored its potential as an MC1R-targeted therapeutic peptide for melanoma treatment in the future. The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of 67Cu-NOTA-PEG2Nle-CycMSHhex {67Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} and 67Cu-NOTA-GGNle-CycMSHhex {67Cu-NOTA-GlyGlyNle-CycMSHhex} on melanoma-bearing mice. NOTA-PEG2Nle-CycMSHhex and NOTA-GGNle-CycMSHhex were synthesized and purified by HPLC. The biodistribution of 67Cu-NOTA-PEG2Nle-CycMSHhex and 67Cu-NOTA-GGNle-CycMSHhex was determined in B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of 67Cu-NOTA-PEG2Nle-CycMSHhex was further examined in B16/F10 melanoma-bearing C57 mice. 67Cu-NOTA-PEG2Nle-CycMSHhex exhibited higher tumor uptake than 67Cu-NOTA-GGNle-CycMSHhex at 2, 4, and 24 h post-injection. The tumor uptake of 67Cu-NOTA-PEG2Nle-CycMSHhex was 27.97 ± 1.98, 24.10 ± 1.83, and 9.13 ± 1.66% ID/g at 2, 4, and 24 h post-injection, respectively. Normal organ uptake of 67Cu-NOTA-PEG2Nle-CycMSHhex was lower than 2.6% ID/g at 4 h post-injection, except for kidney uptake. The renal uptake of 67Cu-NOTA-PEG2Nle-CycMSHhex was 6.43 ± 1.31, 2.60 ± 0.79, and 0.90 ± 0.18% ID/g at 2, 4, and 24 h post-injection, respectively. 67Cu-NOTA-PEG2Nle-CycMSHhex showed high tumor to normal organ uptake ratios after 2 h post-injection. The B16/F10 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT) using 67Cu-NOTA-PEG2Nle-CycMSHhex as an imaging probe at 4 h post-injection. The favorable tumor targeting and biodistribution properties of 67Cu-NOTA-PEG2Nle-CycMSHhex underscored its potential as an MC1R-targeted therapeutic peptide for melanoma treatment. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effect of linker on tumor targeting and biodistribution of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex { 64 Cu-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH 2 } and 64 Cu-NOTA-AocNle-CycMSH hex { 64 Cu-NOTA-8-aminooctanoic acid-Nle-CycMSH hex } on melanoma-bearing mice. NOTA-PEG 2 Nle-CycMSH hex and NOTA-AocNle-CycMSH hex were synthesized and purified by HPLC. The melanocortin-1 (MC1) receptor binding affinities of the peptides were examined on B16/F10 melanoma cells. The biodistributions of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex and 64 Cu-NOTA-AocNle-CycMSH hex were determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex was further examined on B16/F10 melanoma-bearing C57 mice because of its higher melanoma uptake than 64 Cu-NOTA-AocNle-CycMSH hex . The IC 50 values of NOTA-PEG 2 Nle-CycMSH hex and NOTA-AocNle-CycMSH hex were 1.24 ± 0.07 and 2.75 ± 0.48 nM on B10/F10 melanoma cells. 64 Cu-NOTA-PEG 2 Nle-CycMSH hex and 64 Cu-NOTA-AocNle-CycMSH hex were readily prepared with more than 90% radiolabeling yields and showed MC1R-specific binding on B16/F10 cells. 64 Cu-NOTA-PEG 2 Nle-CycMSH hex exhibited higher tumor uptake than 64 Cu-NOTA-AocNle-CycMSH hex at 0.5, 2, 4, and 24 h post-injection. The tumor uptake of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex was 16.23 ± 0.42, 19.59 ± 1.48, 12.83 ± 1.69, and 8.78 ± 2.29% ID/g at 0.5, 2, 4, and 24 h post-injection, respectively. Normal organ uptake of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex was lower than 2% ID/g at 2 h post-injection except for kidney uptake. The renal uptake of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex was 3.66 ± 0.52, 3.27 ± 0.52, and 1.47 ± 0.56 ID/g at 2, 4, and 24 h post-injection, respectively. 64 Cu-NOTA-PEG 2 Nle-CycMSH hex showed high tumor to normal organ uptake ratios after 2 h post-injection. The B16/F10 melanoma lesions could be clearly visualized by positron emission tomography (PET) using 64 Cu-NOTA-PEG 2 Nle-CycMSH hex as an imaging probe at 2 h post-injection. High tumor uptake and low kidney uptake of 64 Cu-NOTA-PEG 2 Nle-CycMSH hex underscored its potential as an MC1R-targeted theranostic peptide for melanoma imaging and therapy.