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

Journal of Nuclear Medicine

Nellie K. Owen¹  Yubin Miao¹  JianQing Chen¹  Thomas P. Quinn¹  Silvia S. Jurisson¹  Timothy J. Hoffman¹  Zhen Cheng¹ 

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

关键词: peptide;    α-melanocyte-stimulating hormone;    ¹¹¹In labeling;    metal cyclization;    melanoma targeting;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

The aim of this study was to examine the effect of rhenium-mediated peptide cyclization on melanoma targeting, biodistribution, and clearance kinetics of the α-melanocyte-stimulating hormone (α-MSH) analog 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled ReO-cyclized [Cys3,4,10,d-Phe7]α-MSH3–13 (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-[Cys4,10,d-Phe7]α-MSH4–13 (CMSH). DOTA was also conjugated to the amino terminus of one of the highest-affinity α-MSH receptor-binding peptides, [Nle4,d-Phe7]α-MSH (NDP), as a linear peptide standard. The DOTA-conjugated α-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–α-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.

【 授权许可】

Unknown