Effects of Polyethylene Glycol and 8-Aminooctanoic Acid Linkers on Melanoma Uptake of [ 99m Tc]Tc-Tricarbonyl-NOTA-Conjugated Lactam-Cyclized α-MSH Peptides.

The purpose of this study was to evaluate the effect of linkers on tumor targeting and biodistribution of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex {[ 99m Tc]Tc(CO) 3 -1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-polyethylene glycol-Nle-c[Asp-His-d-Phe-Arg-Trp-Lys]-CONH 2 } and [ 99m Tc]Tc(CO) 3 -NOTA-AocNle-CycMSH hex {[ 99m Tc]Tc(CO) 3 -NOTA-8-aminooctanoic acid-Nle-CycMSH hex } on B16/F10 melanoma-bearing mice. NOTA-PEG 2 Nle-CycMSH hex and NOTA-AocNle-CycMSH hex were synthesized and radiolabeled with [ 99m Tc]Tc via the {[ 99m Tc]Tc(CO) 3 (OH 2 ) 3 } + intermediate. The biodistribution of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex and [ 99m Tc]Tc(CO) 3 -NOTA-AocNle-CycMSH hex was determined on B16/F10 melanoma-bearing C57 mice. The melanoma imaging property of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex was determined on B16/F10 melanoma-bearing C57 mice. [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex and [ 99m Tc]Tc(CO) 3 -NOTA-AocNle-CycMSH hex were readily prepared with more than 90% radiochemical yields and exhibited MC1R-specific binding on B16/F10 melanoma cells. [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex exhibited a higher tumor uptake than [ 99m Tc]Tc(CO) 3 -NOTA-AocNle-CycMSH hex at 2, 4, and 24 h postinjection. The tumor uptake of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex was 13.63 ± 1.13, 31.93 ± 2.57, 20.31 ± 3.23, and 1.33 ± 0.15% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. The tumor uptake of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex was 1.6 and 3.4 times the tumor uptake of [ 99m Tc]Tc(CO) 3 -NOTA-AocNle-CycMSH hex at 2 and 4 h postinjection, respectively. Meanwhile, the normal organ uptake of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex was lower than 1.8% ID/g at 2 h postinjection. The renal uptake of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex was only 1.73 ± 0.37, 0.73 ± 0.14, and 0.03 ± 0.01% ID/g at 2, 4, and 24 h postinjection, respectively. [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex showed high tumor to normal organ uptake ratios at 2 h postinjection. Single-photon emission computed tomography imaging revealed that the B16/F10 melanoma lesions could be clearly visualized by [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex at 2 h postinjection. Overall, the high tumor uptake and low kidney uptake of [ 99m Tc]Tc(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex highlighted its potential for melanoma imaging and warranted the future evaluation of [ 188 Re]Re(CO) 3 -NOTA-PEG 2 Nle-CycMSH hex for melanoma therapy.