TY - JOUR T1 - Effects of the Amino Acid Linkers on the Melanoma-Targeting and Pharmacokinetic Properties of <sup>111</sup>In-Labeled Lactam Bridge–Cyclized α-MSH Peptides JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 608 LP - 616 DO - 10.2967/jnumed.110.086009 VL - 52 IS - 4 AU - Haixun Guo AU - Jianquan Yang AU - Fabio Gallazzi AU - Yubin Miao Y1 - 2011/04/01 UR - http://jnm.snmjournals.org/content/52/4/608.abstract N2 - The purpose of this study was to examine the profound effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of 111In-labeled lactam bridge–cyclized DOTA-[X]-CycMSHhex {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[X]-c[Asp-His-dPhe-Arg-Trp-Lys]-CONH2; X = GGNle, GENle, or NleGE; GG = -Gly-Gly- and GE = -Gly-Glu-} peptides. Methods: Three novel peptides (DOTA-GGNle-CycMSHhex, DOTA-GENle-CycMSHhex, and DOTA-NleGE-CycMSHhex) were designed and synthesized. The melanocortin-1 (MC1) receptor–binding affinities of the peptides were determined in B16/F1 melanoma cells. The melanoma-targeting and pharmacokinetic properties of 111In-DOTA-GGNle-CycMSHhex and 111In-DOTA-GENle-CycMSHhex were determined in B16/F1 melanoma–bearing C57 mice. Results: DOTA-GGNle-CycMSHhex and DOTA-GENle-CycMSHhex displayed 2.1 and 11.5 nM MC1 receptor–binding affinities, whereas DOTA-NleGE-CycMSHhex showed 873.4 nM MC1 receptor–binding affinity. The introduction of the -GG- linker maintained high melanoma uptake while decreasing kidney and liver uptake of 111In-DOTA-GGNle-CycMSHhex. The tumor uptake of 111In-DOTA-GGNle-CycMSHhex was 19.05 ± 5.04 and 18.6 ± 3.56 percentage injected dose per gram at 2 and 4 h after injection, respectively. 111In-DOTA-GGNle-CycMSHhex exhibited 28%, 32%, and 42% less kidney uptake than 111In-DOTA-Nle-CycMSHhex we reported previously, and 61%, 65%, and 68% less liver uptake than 111In-DOTA-Nle-CycMSHhex at 2, 4, and 24 h after injection, respectively. Conclusion: The amino acid linkers exhibited profound effects on the melanoma-targeting and pharmacokinetic properties of the 111In-labeled lactam bridge–cyclized α-melanocyte–stimulating hormone peptides. Introduction of the -GG- linker maintained high melanoma uptake while reducing kidney and liver uptake of 111In-DOTA-GGNle-CycMSHhex, highlighting its potential as an effective imaging probe for melanoma detection, as well as a therapeutic peptide for melanoma treatment when labeled with a therapeutic radionuclide. ER -