title: Evaluation of an (111)In-DOTA-rhenium cyclized alpha-MSH analog: a novel cyclic-peptide analog with improved tumor-targeting properties.
abstract: The aim of this study was to examine the effect of rhenium-mediated peptide cyclization on melanoma targeting, biodistribution, and clearance kinetics of the alpha-melanocyte-stimulating hormone (alpha-MSH) analog 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled ReO-cyclized [Cys(3,4,10),D-Phe(7)]alpha-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-Phe(7)]alpha-MSH(4-13) (CMSH). DOTA was also conjugated to the amino terminus of one of the highest-affinity alpha-MSH receptor-binding peptides, [Nle(4),D-Phe(7)]alpha-MSH (NDP), as a linear peptide standard. The DOTA-conjugated alpha-MSH analogs were radiolabeled with (111)In 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 (111)In-DOTA-ReCCMSH were significantly higher than those of the other closely related (111)In-DOTA-alpha-MSH conjugates. Even at 24 h after injection, a comparison of the tumor uptake values for (111)In-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 (111)In-DOTA-ReCCMSH (8.98 +/- 0.82 %ID/g) than of (111)In-DOTA-CCMSH (63.2 +/- 15.6 %ID/g), (111)In-DOTA-CMSH (38.4 +/- 3.6 %ID/g), and (111)In-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 (111)In-DOTA-ReCCMSH (e.g., 489, 159, 100, and 49 for blood, muscle, lung, and liver, respectively, at 4 h after injection).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry, University of Missouri-Columbia, 65211, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: Z
authors.initials: Z
authors.lastname: Cheng
authors.forename: N K
authors.initials: NK
authors.lastname: Owen
authors.forename: T J
authors.initials: TJ
authors.lastname: Hoffman
authors.forename: Y
authors.initials: Y
authors.lastname: Miao
authors.forename: S S
authors.initials: SS
authors.lastname: Jurisson
authors.forename: T P
authors.initials: TP
authors.lastname: Quinn
mesh_terms: D000818:Animals; D005260:Female; D007205:Indium Radioisotopes / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging*; D051379:Mice; D008810:Mice, Inbred C57BL; D009942:Organometallic Compounds / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000627:therapeutic use; D012211:Rhenium; D014018:Tissue Distribution; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000627:therapeutic use*
chemical_list: C444302:1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (Cys(3,4,10),D-Phe(7))alpha-MSH(3-13); D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D000521:alpha-MSH; D012211:Rhenium