[IN-111]-DTPA-LABELED ANALOGS OF ALPHA-MELANOCYTE-STIMULATING HORMONEFOR MELANOMA TARGETING - RECEPTOR-BINDING IN-VITRO AND IN-VIVO

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 Ly s(10) amino side chain were coupled to diethylenetriaminepentaacetic a cid (DTPA, a chelator for In-111) in monomeric and dimeric forms and t ested for their binding activity and bioactivity in vitro with mouse a nd human melanoma cell lines and by receptor autoradiography to tumor sections, as well as in vivo with normal and melanoma-bearing mice: As p(5),D-Phe(7),Lys(mono-DHP)(10)]-alpha-MSH(4-10, -[Nle(4),Asp(5),D-Phe (7),Lys(10)]-alpha-MSH(4-10), Asp(5),D-Phe(7),Lys(bis-DHP)(10)]-alpha- MSH(4-10), sp(5),D-Phe(7),Lys(mono-DHP)(10)]-alpha-MSH(4-10)} and [Nle (4),Asp(5),D-Phe(7),Lys(10)]-alpha-MSH(4-10)}. In the receptor-binding assays with B16-F1 mouse and D10 human melanoma cells, the K-D val 0. 76 and 31.17 nM and in the melanin bioassay the results were similar ( EC(50) values between 0.15 and 4.40 nM). The tissue distribution of th e In-111-labeled compounds in C57Bl/6J mice showed that the dimeric [I n-111]- Asp(5),D-Phe(7),Lys(bis-DHP?(10))]-alpha-MSH(4-10) exhibited t he lowest non-specific binding. In mice carrying B16-F1 melanoma tumor s, the monomeric compound displayed 2-fold higher In-111 uptake by the tumor and much lower non-specific uptake by the liver (12-fold) and t he kidneys (2.5 -fold) than the dimeric derivative . This demonstrates that modification of the Lys(10) side chain by DHP is a promising lea d for new MSH radiopharmaceuticals for melanoma targeting. (C) 1994 Wi ley-Liss, Inc.