[111In]-DTPA-labeled analogues of alpha-melanocyte-stimulating hormone for melanoma targeting: receptor binding in...

Six alpha-MSH(4-10) [Nle-Asp-His-D-Phe-Arg-Trp-Lys-amide] derivatives carrying 2 or 1 or no 2,3-dihydroxy-(2S)-propyl (DHP) groups on the Lys10 amino side chain were coupled to diethylene-triaminopentaacetic acid (DTPA, a chelator for 111In) in monomeric and dimeric forms and tested for their binding activity and bioactivity in vitro with mouse and human melanoma cell lines and by receptor autoradiography to tumor sections, as well as in vivo with normal and melanoma-bearing mice: DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10),DTPA-[Nle4, Asp5, D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10), DTPA[Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10), DTPA-bis-([Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10)), DTPA-bis[([Nle4,Asp5,D-Phe7,Lys(mono-DHP)10]-alpha-MSH(4-10)) and DTPA-bis-([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)). In the receptor-binding assays with B16-F1 mouse and D10 human melanoma cells, the KD values ranged between 0.76 and 31.17 nM and in the melanin bioassay the results were similar (EC50 values between 0.15 and 4.40 nM). The tissue distribution of the 111In-labeled compounds in C57Bl/6J mice showed that the dimeric [111In]-DTPA-bis([Nle4,Asp5,D-Phe7,Lys10]-alpha-MSH(4-10)) and the monomeric [111In]-DTPA-[Nle4,Asp5,D-Phe7,Lys(bis-DHP)10]-alpha-MSH(4-10) exhibited the lowest non-specific binding. In mice carrying B16-F1 melanoma tumors, the monomeric compound displayed 2-fold higher 111In uptake by the tumor and a much lower non-specific uptake by the liver (12-fold) and the kidneys (2.5-fold) than the dimeric derivative. This demonstrates that modification of the Lys10 side chain by DHP is a promising lead for new MSH radiopharmaceuticals for melanoma targeting.