Reducing renal uptake of 90Y- and 177Lu-labeled alpha-melanocyte stimulating hormone peptide analogues

Objective: The purpose of this study was to improve the tumor-to-kidney uptake ratios of Y-90- and Lu-177-[1,4,7, 10-tetraazacyclododecane 1,4,7, 1 0-tetraacetic acid-Re-Cys 3,4,10, D-Phe 7, Arg(11)]alpha-melanocyte stimulating hormone(3-13) {DOTA-Re(Arg(11))CCMSH} through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. Methods: A new peptide of DOTA-Re(Glu 2, Arg(11))CCMSH was designed, synthesized and labeled with Y-90 and Lu-177. Pharmacokinetics of Y-90- and Lu-177-DOTA-Re(Glu(2), Arg(11))CCMSH was determined in B16/FI murine melanoma-bearing C57 mice. Results: Y-90- and Lu-177-DOTA-Re(Glu(2), Arg(11))CCMSH exhibited significantly (P <.05) less renal uptake values than Y-90- and Lu-177-DOTA-Re(Arg(11))CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The renal uptake values of Y-90- and Lu-177-DOTA-Re(Glu(2), Arg(11))CCMSH were 28.16% and 28.81% of those of Y-90- and Lu-177-DOTA-Re(Arg(11))CCMSH, respectively, at 4 h postinjection. Y-90- and Lu-177-DOTA-Re(Glu(2), Arg(11))CCMSH displayed higher tumor-to-kidney uptake ratios than Y-90- and Lu-177-DOTA-Re(Arg(11))CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The tumor-to-kidney uptake ratio of Y-90- and Lu-177-DOTA-Re(Glu 2, Arg(11))CCMSH was 2.28 and 1.69 times of Y-90- and Lu-177-DOTA-Re(Arg(11))CCMSH, respectively, at 4 h postinjection. The Y-90- and Lu-177-DOTA-Re(Glu(2), Arg(11))CCMSH activity accumulation was low in normal organs except for kidney. Conclusions: Coupling a negatively charged amino acid (Glu) to the CCMSH peptide sequence dramatically reduced the renal uptake values and increased the tumor-to-kidney uptake ratios of Y-90- and Lu-177-DOTA-Re(Glu(2), Arg(11))CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma. (c) 2006 Elsevier Inc. All rights reserved.