title: A novel DOTA-alpha-melanocyte-stimulating hormone analog for metastatic melanoma diagnosis.
abstract: Scintigraphic imaging of metastatic melanoma lesions requires highly tumor-specific radiolabeled compounds. Because both melanotic and amelanotic melanomas overexpress receptors for alpha-melanocyte-stimulating hormone (alpha-MSH; receptor name: melanocortin type 1 receptor, or MC1R), radiolabeled alpha-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a melanoma-selective radiolabeled alpha-MSH analog suitable for melanoma diagnosis.
  
  
  METHODS
  The very potent alpha-MSH analog [Nle(4), D-Phe(7)]-alpha-MSH (NDP-MSH) and a newly designed alpha-MSH octapeptide analog, [betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (MSH(oct)), were conjugated to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to enable radiometal incorporation. The resulting DOTA conjugates were evaluated in vitro for their MC1R-binding affinity and melanogenic activity in isolated mouse B16F1 cells and in vivo for their biodistribution in mouse models of primary and metastatic melanoma after labeling with (111)In.
  
  
  RESULTS
  DOTA-MSH(oct) was shown to bind with high affinity (inhibitory concentration of 50% [IC(50)] = 9.21 nmol/L) to the MC1R, although with lower potency than does DOTA-NDP-MSH (IC(50) = 0.25 nmol/L). In B16F1 melanoma-bearing mice, both (111)In-DOTA-NDP-MSH and (111)In-DOTA-MSH(oct) exhibited high MC1R-mediated uptake by melanoma, which differed by a factor of only 1.5 at 4 h after injection. The main route of excretion for both radioconjugates was the kidneys, whereby (111)In-DOTA-MSH(oct) led to somewhat higher kidney values than did (111)In-DOTA-NDP-MSH. In contrast, the latter was much more poorly cleared from other nonmalignant tissues, including bone, the most radiosensitive organ. Therefore, (111)In-DOTA-MSH(oct) displayed higher uptake ratios of tumor to nontarget tissue (e.g., tumor-to-bone ratio 4 h after injection was 4.9 for (111)In-DOTA-NDP-MSH and 53.9 for (111)In-DOTA-MSH(oct)). Lung and liver melanoma metastases could easily be visualized on tissue section autoradiographs after injection of (111)In-DOTA-MSH(oct). Radio-reversed-phase high-performance liquid chromatography analysis of urine samples revealed that most (111)In-DOTA-MSH(oct) is excreted intact 4 h after injection, indicating good in vivo stability.
  
  
  CONCLUSIONS
  (111)In-DOTA-MSH(oct) exhibits more favorable overall performance than does (111)In-DOTA-NDP-MSH in murine models of primary and metastatic melanoma, making it a promising melanoma imaging agent.
authors.affiliation: Laboratory of Endocrinology, Department of Research, University Hospital and University Children's Hospital, Basel, Switzerland. sylvie.froidevaux@unibas.ch
authors.forename: Sylvie
authors.initials: S
authors.lastname: Froidevaux
authors.forename: Martine
authors.initials: M
authors.lastname: Calame-Christe
authors.forename: Heidi
authors.initials: H
authors.lastname: Tanner
authors.forename: Lazar
authors.initials: L
authors.lastname: Sumanovski
authors.forename: Alex N
authors.initials: AN
authors.lastname: Eberle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001345:Autoradiography; D004355:Drug Stability; D005260:Female; D007205:Indium Radioisotopes; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D018043:Receptors, Corticotropin / Q000032:analysis*; D044101:Receptors, Melanocortin; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D000521:alpha-MSH / Q000031:analogs & derivatives*
chemical_list: D007205:Indium Radioisotopes; D019275:Radiopharmaceuticals; D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D000521:alpha-MSH