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Evaluation of an ¹¹¹In-DOTA–Rhenium Cyclized -MSH Analog: A Novel Cyclic-Peptide Analog with Improved Tumor-Targeting Properties

Departments of Biochemistry, Radiology, and Chemistry, University of Missouri–Columbia, Columbia; and Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri

The aim of this study was to examine the effect of rhenium-mediated peptide cyclization on melanoma targeting, biodistribution, and clearance kinetics of the -melanocyte-stimulating hormone (-MSH) analog 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled ReO-cyclized [Cys^3,4,10,D-Phe⁷]-MSH_3–13 (DOTA-ReCCMSH). Methods: DOTA-ReCCMSH was compared with its reduced nonmetalated linear homolog, DOTA-CCMSH, and an analog in which rhenium cyclization was replaced by disulfide bond cyclization, DOTA-[Cys^4,10,D-Phe⁷]-MSH_4–13 (CMSH). DOTA was also conjugated to the amino terminus of one of the highest-affinity -MSH receptor-binding peptides, [Nle⁴,D-Phe⁷]-MSH (NDP), as a linear peptide standard. The DOTA-conjugated -MSH analogs were radiolabeled with ¹¹¹In and examined for their in vitro receptor-binding affinity with B16/F1 murine melanoma cells, and their in vivo biodistribution properties were evaluated and compared in melanoma tumor–bearing C57 mice. Results: The tumor uptake values of ¹¹¹In-DOTA–ReCCMSH were significantly higher than those of the other closely related ¹¹¹In-DOTA–-MSH conjugates. Even at 24 h after injection, a comparison of the tumor uptake values for ¹¹¹In-DOTA-coupled ReCCMSH (4.86 ± 1.52 percentage injected dose [%ID]/g), CCMSH (1.91 ± 0.56 %ID/g), CMSH (3.09 ± 0.32 %ID/g), and NDP (2.47 ± 0.79 %ID/g) highlighted the high tumor retention property of ReCCMSH. Rhenium-coordinated cyclization resulted in less renal radioactivity accumulation of ¹¹¹In-DOTA–ReCCMSH (8.98 ± 0.82 %ID/g) than of ¹¹¹In-DOTA–CCMSH (63.2 ± 15.6 %ID/g), ¹¹¹In-DOTA–CMSH (38.4 ± 3.6 %ID/g), and ¹¹¹In-DOTA–NDP (12.0 ± 1.96 %ID/g) at 2 h after injection and significantly increased its clearance into the urine (92 %ID at 2 h after injection). A high radioactivity uptake ratio of tumor to normal tissue was obtained for ¹¹¹In-DOTA–ReCCMSH (e.g., 489, 159, 100, and 49 for blood, muscle, lung, and liver, respectively, at 4 h after injection). Conclusion: The novel ReO-coordinated cyclic structure of DOTA-ReCCMSH contributes significantly to its enhanced tumor-targeting and renal clearance properties and makes DOTAReCCMSH an excellent candidate for melanoma radiodetection and radiotherapy.

Key Words: peptide • -melanocyte-stimulating hormone • ¹¹¹In labeling • metal cyclization • melanoma targeting

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