title: A gallium-labeled DOTA-alpha-melanocyte- stimulating hormone analog for PET imaging of melanoma metastases.
abstract: Although (18)F-FDG PET is widely used for metastatic melanoma diagnosis, it is less accurate than desirable, particularly for small foci. Since both melanotic and amelanotic melanomas overexpress receptors for alpha-melanocyte-stimulating hormone (alpha-MSH; receptor name, melanocortin type 1 receptor [MC1R]), radiolabeled alpha-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a positron emitter-labeled alpha-MSH analog suitable for PET imaging of melanoma metastases.
  
  
  METHODS
  A short linear alpha-MSH analog, [Nle(4),Asp(5),D-Phe(7)]-alpha-MSH(4-11) (NAPamide), was newly designed and conjugated to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to enable radiometal incorporation. Compared with our previously reported DOTA-alpha-MSH analog, DOTA-MSH(oct) ([DOTA-betaAla(3),Nle(4),Asp(5),D-Phe(7),Lys(10)]-alpha-MSH(3-10)), the major modification lies in the conjugation of DOTA to the C-terminal end of the peptide via the epsilon-amino group of Lys(11), as opposed to the N-terminal alpha-amino group. After labeling with (111)In, (67)Ga, and the short-lived positron emitter (68)Ga, DOTA-NAPamide was characterized in vitro and in vivo using the mouse melanoma B16F1cell line.
  
  
  RESULTS
  DOTA-NAPamide exhibited an almost 7-fold higher MC1R binding potency as compared with DOTA-MSH(oct). In B16F1 melanoma-bearing mice, both (111)In-DOTA-NAPamide and (67)Ga-DOTA-NAPamide behaved more favorably than (111)In-DOTA-MSH(oct). Both radiopeptides exhibited higher tumor and lower kidney uptake leading to tumor-to-kidney ratios of the 4- to 48-h area under the curve that were 4.6 times ((111)In) and 7.5 times ((67)Ga) greater than that obtained with (111)In-DOTA-MSH(oct). In addition, the 4-h kidney uptake of (67)Ga-DOTA-NAPamide could be reduced by 64% by coinjection of 15 mg L-lysine, without affecting tumor uptake. Skin primary melanoma as well as lung and liver melanoma metastases could be easily visualized on tissue section autoradiographs after systemic injection of (67)Ga-DOTA-NAPamide. The melanoma selectivity of DOTA-NAPamide was confirmed by PET imaging studies using (68)Ga-DOTA-NAPamide. Tumor uptake was found to be highest when the smallest amount of peptide was administered.
  
  
  CONCLUSIONS
  DOTA-NAPamide labeled with either (111)In or (67)Ga/(68)Ga is in every way superior to (111)In-DOTA-MSH(oct) in murine models of primary and metastatic melanoma, which makes it a promising agent for melanoma targeting. High-contrast images obtained in PET studies with an experimental tumor model 1 h after injection augurs well for its clinical potential as an imaging tool.
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: Jochen
authors.initials: J
authors.lastname: Schuhmacher
authors.forename: Heidi
authors.initials: H
authors.lastname: Tanner
authors.forename: Rainer
authors.initials: R
authors.lastname: Saffrich
authors.forename: Markus
authors.initials: M
authors.lastname: Henze
authors.forename: Alex N
authors.initials: AN
authors.lastname: Eberle
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000556:secondary*; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012878:Skin Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed / Q000379:methods*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: C483473:(111)indium-alpha-MSH (3-10), DOTA-beta-Ala(3)-Nle(4)-Asp(5)-Phe(7)-Lys(10)-; D009942:Organometallic Compounds; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; C521500:alpha-MSH (4-11), acetyl0Nle(4)-Asp(5)-Phe(7)-; C483472:gadolinium alpha-MSH (4-11), Nle(4)-Asp(5)-Phe(7)-epsilon(DOTA)Lys(11)-; D000521:alpha-MSH