Design and evaluation of new Tc-99m-labeled lactam bridge-cyclized alpha-MSH peptides for melanoma imaging

The purpose of this study was to examine the melanoma targeting and imaging properties of new ^99mTc-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (α-MSH) peptides using bifunctional chelating agents. MAG₃-GGNle-CycMSH_hex, AcCG ₃-GGNle-CycMSH_hex, and HYNIC-GGNle-CycMSH_hex peptides were synthesized, and their melanocortin-1 (MC1) receptor binding affinities were determined in B16/F1 melanoma cells. The biodistribution of ^99mTc-MAG₃-GGNle-CycMSH_hex, ^99mTc-AcCG₃-GGNle-CycMSH_hex, ^99mTc(CO)₃-HYNIC-GGNle-CycMSH_hex, and ^99mTc(EDDA)-HYNIC-GGNle-CycMSH_hex were determined in B16/F1 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of ^99mTc(EDDA)-HYNIC-GGNle-CycMSH_hex were further examined because of its high melanoma uptake and fast urinary clearance. The IC ₅₀ values of MAG₃-GGNle-CycMSH_hex, AcCG ₃-GGNle-CycMSH_hex, and HYNIC-GGNle-CycMSH_hex were 1.0 ± 0.05, 1.2 ± 0.19, and 0.6 ± 0.04 nM in B16/F1 melanoma cells, respectively. Among these four ^99mTc-peptides, ^99mTc(EDDA)-HYNIC-GGNle-CycMSH_hex exhibited the highest melanoma uptake (14.14 ± 4.90% ID/g) and fastest urinary clearance (91.26 ± 1.96% ID) at 2 h postinjection. ^99mTc(EDDA)-HYNIC-GGNle- CycMSH_hex showed high tumor to normal organ uptake ratios except for the kidneys. The tumor/kidney uptake ratios of ^99mTc(EDDA)-HYNIC- GGNle-CycMSH_hex were 2.50 and 3.55 at 4 and 24 h postinjection. The melanoma lesions were clearly visualized by SPECT/CT using ^99mTc(EDDA)-HYNIC-GGNle-CycMSH_hex as an imaging probe at 2 h postinjection. Overall, high melanoma uptake coupled with fast urinary clearance of ^99mTc(EDDA)-HYNIC-GGNle-CycMSH_hex highlighted its potential for metastatic melanoma detection in the future.