Novel Al¹⁸F-NOTA-Conjugated Lactam-Cyclized α-Melanocyte-Stimulating Hormone Peptides with Enhanced Melanoma Uptake

The purpose of this study was to evaluate the effect of linker on tumor targeting and biodistribution of Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex {Al¹⁸F-1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-poly(ethylene glycol)-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH₂} and Al¹⁸F-NOTA-AocNle-CycMSH_hex {Al¹⁸F-NOTA-8-aminooctanoic acid-Nle-CycMSH_hex} on melanoma-bearing mice. NOTA-PEG₂Nle-CycMSH_hex and NOTA-AocNle-CycMSH_hex were synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex and Al¹⁸F-NOTA-AocNle-CycMSH_hex was determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex was further examined on B16/F10 melanoma-bearing C57 mice because of its higher melanoma uptake and lower renal uptake than that of Al¹⁸F-NOTA-AocNle-CycMSH_hex. The IC₅₀ values of NOTA-PEG₂/AocNle-CycMSH_hex were 1.24 ± 0.07 and 2.75 ± 0.48 nM on B10/F10 cells. Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex and Al¹⁸F-NOTA-AocNle-CycMSH_hex were readily prepared with more than 55% of radiolabeling yields and displayed melanocortin-1 receptor (MC1R)-specific binding on B16/F10 cells. Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex exhibited higher tumor uptake and lower kidney and liver uptake than Al¹⁸F-NOTA-AocNle-CycMSH_hex at 1 and 2 h post injection. The tumor and renal uptakes of Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex were 17.44 ± 0.76 and 2.07 ± 0.43% ID/g at 1 h post injection, respectively. Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex showed the high tumor to normal organ uptake ratios after 1 h post injection. The B16/F10 melanoma lesions could be clearly visualized by positron emission tomography (PET) using Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex as an imaging probe at 1 and 2 h post injection. Overall, high tumor uptake, low kidney and liver uptake, and fast urinary clearance of Al¹⁸F-NOTA-PEG₂Nle-CycMSH_hex highlighted its potential as an MC1R-targeted imaging probe for melanoma detection.