title: Melanoma targeting with DOTA-alpha-melanocyte-stimulating hormone analogs: structural parameters affecting tumor uptake and kidney uptake.
abstract: Radiolabeled analogs of alpha-melanocyte-stimulating hormone (alpha-MSH) are potential candidates for the diagnosis and therapy of melanoma metastases. After our recent observation that a linear octapeptide alpha-MSH analog incorporating the metal chelator 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) at the C-terminal lysine, [Nle(4),Asp(5),d-Phe(7),Lys(11)(DOTA)]-alpha-MSH(4-11) (DOTA-NAPamide), showed high accumulation in melanomas in a mouse model, low uptake in normal tissues, and moderate uptake in the kidneys, we attempted to identify the structural parameters influencing tumor uptake versus kidney uptake.
  
  
  METHODS
  We designed a series of novel DOTA-alpha-MSH analogs differing from DOTA-NAPamide by small alterations, such as the position of DOTA in the peptide, hydrophobicity, and charge, by modifying the C-terminal Lys(11) residue. They were evaluated both for their melanocortin type 1 receptor (MC1R)-binding potency and for their biodistribution by use of the B16F1 melanoma mouse model.
  
  
  RESULTS
  When DOTA was shifted to the N terminus of the peptide, a 3-fold increase in kidney retention was obtained. However, when the epsilon-amino group of the Lys(11) residue was acetylated in addition to the DOTA relocation, kidney uptake returned to the low values obtained with DOTA-NAPamide; this result indicated that neutralization of the epsilon-amino group positive charge of the Lys(11) residue rather than the position of DOTA accounted for the low kidney retention. Unexpectedly, no further reduction in kidney uptake was obtained by the introduction of 1 or 2 negative charges on Lys(11). Melanoma uptake was in accordance with MC1R affinity; the highest values were obtained for peptides bearing carboxy-terminal amidation and positioning of DOTA.
  
  
  CONCLUSIONS
  The kidney uptake of DOTA-alpha-MSH analogs could be considerably reduced, without affecting MC1R affinity, by altering (neutralizing) the charge of the Lys(11) residue. Accordingly, the resulting peptides exhibited a high ratio of tumor uptake to kidney uptake that is favorable for diagnostic and therapeutic applications. These structure-activity data may help to improve the performance of DOTA-alpha-MSH analogs and other radiopeptides.
authors.affiliation: Laboratory of Endocrinology, Department of Research, University Hospital and University Children's Hospital, Basel, Switzerland. sylvie.froidevaux@actelion.com
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: Alex N
authors.initials: AN
authors.lastname: Eberle
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007668:Kidney / Q000000981:diagnostic imaging / Q000378:metabolism*; D008545:Melanoma / Q000000981:diagnostic imaging / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D000521:alpha-MSH