title: DOTA alpha-melanocyte-stimulating hormone analogues for imaging metastatic melanoma lesions.
abstract: Scintigraphic imaging of metastatic melanoma lesions requires highly tumor-specific radiopharmaceuticals. Because both melanotic and amelanotic melanomas overexpress melanocortin-1 receptors (MC1R), radiolabeled analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) are potential candidates for melanoma diagnosis. Here, we report the in vivo performance of a newly designed octapeptide analogue, [betaAla(3), Nle(4), Asp(5), D-Phe(7), Lys(10)]-alpha-MSH(3-10) (MSH(OCT)), which was conjugated through its N-terminal amino group to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to enable incorporation of radiometals (e.g., indium-111) into the peptide. DOTA-MSH(OCT) displayed high in vitro MC1R affinity (IC(50) 9.21 nM). In vivo [(111)In]DOTA-MSH(OCT) exhibited a favorable biodistribution profile after injection in B16-F1 tumorbearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [(111)In]DOTA-MSH(OCT). A comparative study of [(111)In]DOTA-MSH(OCT) with [(111)In]DOTA-[Nle(4), D-Phe(7)]-alpha-MSH ([(111)In]-DOTA-NDP-MSH) demonstrated the superiority of the DOTA-MSH(OCT) peptide, particularly for the amount of radioactivity taken up by nonmalignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [(111)In]DOTA-MSH(OCT) is a promising melanoma imaging agent.
authors.affiliation: Department of Research, University Hospital and University Children's Hospital, CH-4031, 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: Lazar
authors.initials: L
authors.lastname: Sumanovski
authors.forename: Heidi
authors.initials: H
authors.lastname: Tanner
authors.forename: Alex N
authors.initials: AN
authors.lastname: Eberle
mesh_terms: D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism*; D003952:Diagnostic Imaging; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism*; D014018:Tissue Distribution; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D000521:alpha-MSH