DOTA α‐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.

64Cu-Labeled Alpha-Melanocyte-Stimulating Hormone Analog for MicroPET Imaging of Melanocortin 1 Receptor Expression

“…Several α-MSH analogs which can recognize the MC1R have been labeled with different radionuclides for melanoma detection and radiotherapy (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28). The most promising melanoma-targeting peptides are linear peptide NAPamide (16) and rhenium-cyclized CCMSH peptides (9,11,15).…”

Radioiodination of Rhenium Cyclized α-Melanocyte-Stimulating Hormone Resulting in Enhanced Radioactivity Localization and Retention in Melanoma

“…␣-MSH receptors display nanomolar to subnanomolar affinities for ␣-MSH peptides and are rapidly internalized on ligand binding (21,22). High receptor affinity and specificity make ␣-MSH peptide analogs attractive vehicles for delivering radionuclides to melanoma cells (23)(24)(25). Efforts to develop radiohalogenated ␣-MSH analogs for melanoma targeting have been disappointing for the most part.…”

68Ga-Labeled Radiopharmaceuticals for Positron Emission Tomography

“…In particular, 68 Ga-DOTA-rheniumcyclized alphamelanocyte-stimulating hormone (alpha-MSH) analogue [DOTA-ReCCMSH (Arg11)] is a promising agent for the early detection of melanoma in mice [37]. Likewise, 68 Ga-DOTA-NAPamide, a short linear alpha-MSH analogue, has been reported to be superior to 111 In-DOTA-MSH for the targeting of melanocortin type 1 receptor in murine models of primary and metastatic melanoma [38]. However, receptor density in human melanoma is much lower than in murine tumor models, and thus, more work is needed to improve receptor affinity in man.…”