title: Small-animal PET of melanocortin 1 receptor expression using a 18F-labeled alpha-melanocyte-stimulating hormone analog.
abstract: (18)F-Labeled small synthetic peptides have emerged as attractive probes for imaging various molecular targets with PET. The alpha-melanocyte-stimulating hormone (alpha-MSH) receptor (melanocortin type 1 receptor [MC1R]) is overexpressed in most murine and human melanomas. It is a promising molecular target for diagnosis and therapy of melanomas. However, (18)F compounds have not been successfully developed for imaging the MC1R.
  
  
  METHODS
  In this study, an alpha-MSH analog, Ac-Nle-Asp-His-D-Phe-Arg-Trp-Gly-Lys-NH(2) (NAPamide), was radiolabeled with N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB). The resulting radiopeptide was evaluated as a potential molecular probe for small-animal PET of melanoma and MC1R expression in melanoma xenografted mouse models.
  
  
  RESULTS
  The binding affinity of (19)F-SFB-conjugated NAPamide, (19)F-FB-NAPamide, was determined to be 7.2 +/- 1.2 nM (mean +/- SD) using B16/F10 cells and (125)I-(Tyr(2))-[Nle(4),D-Phe(7)]-alpha-MSH [(125)I-(Tyr(2))-NDP] as a radioligand. The biodistribution of (18)F-FB-NAPamide was then investigated in C57BL/6 mice bearing subcutaneous murine B16/F10 melanoma tumors with high expression of MC1Rs and Fox Chase Scid mice bearing human A375M melanoma with a relatively low number of MC1R receptors. Biodistribution experiments showed that tumor uptake values (percentage injected dose per gram of tumor [%ID/g]) of (18)F-FB-NAPamide were 1.19 +/- 0.11 %ID/g and 0.46 +/- 0.11 %ID/g, in B16/F10 and A375M xenografted melanoma at 1 h after injection, respectively. Furthermore, the B16/F10 tumor uptake was significantly inhibited by coinjection with excess alpha-MSH peptide (P < 0.05), indicating that (18)F-FB-NAPamide specifically recognizes the MC1R in living mice. Small-animal PET of (18)F-FB-NAPamide in mice bearing B16/F10 and A375M tumors at 1 h after tail vein injection revealed good B16/F10 tumor-to-background contrast and low A375M tumor-to-background ratios.
  
  
  CONCLUSIONS
  (18)F-FB-NAPamide is a promising molecular probe for alpha-MSH receptor-positive melanoma PET and warrants further study.
authors.affiliation: Molecular Imaging Program at Stanford, Stanford University, Stanford, California 94305, USA. zcheng@stanford.edu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cheng
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Edward
authors.initials: E
authors.lastname: Graves
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Xiong
authors.forename: Mangal
authors.initials: M
authors.lastname: Dandekar
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Sanjiv Sam
authors.initials: SS
authors.lastname: Gambhir
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005462:Fluorine Radioisotopes; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000378:metabolism / Q000493:pharmacokinetics*; D044102:Receptor, Melanocortin, Type 1 / Q000096:biosynthesis*; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D005462:Fluorine Radioisotopes; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D044102:Receptor, Melanocortin, Type 1; C521500:alpha-MSH (4-11), acetyl0Nle(4)-Asp(5)-Phe(7)-; D000521:alpha-MSH