α–melanocyte‐stimulating hormone peptide analogs labeled with technetium‐99m and indium‐111 for malignant melanoma targeting

BACKGROUND Previous studies have shown that the compact structure of a rhenium‐cyclized α–melanocyte‐stimulating hormone peptide analog, [Cys3, 4, 10,D‐Phe7]α‐MSH 3–13 , or Re‐CCMSH, significantly enhanced its in vivo tumor uptake and retention. In this study, the metal chelate 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) was coupled to the N‐terminus of Re‐CCMSH in order to develop a melanoma‐targeting peptide that could be labeled with a wider variety of imaging and therapeutic radionuclides. METHODS Biodistribution properties of indium‐111 ( 111 In)–labeled DOTA‐Re‐CCMSH were compared with the non‐DOTA‐containing technetium‐99m ( 99m Tc)–CCMSH in murine melanoma–bearing C57 mice to determine the effects of DOTA on tumor uptake and whole‐body clearance. The tumor targeting capacity and clearance kinetics of 111 In‐DOTA‐Re‐CCMSH were also compared with other related cyclic and linear 111 In‐labeled DOTA‐α‐MSH complexes. RESULTS The in vivo distribution data showed that the conjugation of DOTA to Re‐CCMSH did not reduce its initial tumor uptake kinetics but did enhance its tumor retention and renal clearance properties. The tumor uptake of 111 In‐DOTA‐Re‐CCMSH was significantly higher than the other 111 In‐DOTA–coupled cyclic or linear α‐MSH analogs used in this study. Moreover, 111 In‐DOTA‐Re‐CCMSH displayed lower radioactivity accumulation in normal tissues of interest than its non‐Re‐cyclized counterpart, 111 In‐DOTA‐CCMSH; the disulfide bond–cyclized 111 In‐DOTA‐CMSH; or the linear 111 In‐DOTA‐NDP. CONCLUSIONS Peptide cyclization via rhenium coordination significantly enhanced the tumor targeting and renal clearance properties of DOTA‐Re‐CCMSH, making it an excellent candidate for melanoma radiodetection and radiotherapy. Cancer 2002;94:1196–1201. © 2002 American Cancer Society. DOI 10.1002/cncr.10284