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A Novel DOTA--Melanocyte–Stimulating Hormone Analog for Metastatic Melanoma Diagnosis

Laboratory of Endocrinology, Department of Research, University Hospital and University Children’s Hospital, Basel, Switzerland

Scintigraphic imaging of metastatic melanoma lesions requires highly tumor-specific radiolabeled compounds. Because both melanotic and amelanotic melanomas overexpress receptors for -melanocyte–stimulating hormone (-MSH; receptor name: melanocortin type 1 receptor, or MC1R), radiolabeled -MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a melanoma-selective radiolabeled -MSH analog suitable for melanoma diagnosis. Methods: The very potent -MSH analog [Nle⁴, D-Phe⁷]--MSH (NDP-MSH) and a newly designed -MSH octapeptide analog, [ßAla³, Nle⁴, Asp⁵, D-Phe⁷, Lys¹⁰]--MSH_3–10 (MSH_oct), were conjugated to the metal chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to enable radiometal incorporation. The resulting DOTA conjugates were evaluated in vitro for their MC1R-binding affinity and melanogenic activity in isolated mouse B16F1 cells and in vivo for their biodistribution in mouse models of primary and metastatic melanoma after labeling with ¹¹¹In. Results: DOTA-MSH_oct was shown to bind with high affinity (inhibitory concentration of 50% [IC₅₀] = 9.21 nmol/L) to the MC1R, although with lower potency than does DOTA-NDP-MSH (IC₅₀ = 0.25 nmol/L). In B16F1 melanoma-bearing mice, both ¹¹¹In-DOTA-NDP-MSH and ¹¹¹In-DOTA-MSH_oct exhibited high MC1R-mediated uptake by melanoma, which differed by a factor of only 1.5 at 4 h after injection. The main route of excretion for both radioconjugates was the kidneys, whereby ¹¹¹In-DOTA-MSH_oct led to somewhat higher kidney values than did ¹¹¹In-DOTA-NDP-MSH. In contrast, the latter was much more poorly cleared from other nonmalignant tissues, including bone, the most radiosensitive organ. Therefore, ¹¹¹In-DOTA-MSH_oct displayed higher uptake ratios of tumor to nontarget tissue (e.g., tumor-to-bone ratio 4 h after injection was 4.9 for ¹¹¹In-DOTA-NDP-MSH and 53.9 for ¹¹¹In-DOTA-MSH_oct). Lung and liver melanoma metastases could easily be visualized on tissue section autoradiographs after injection of ¹¹¹In-DOTA-MSH_oct. Radio–reversed-phase high-performance liquid chromatography analysis of urine samples revealed that most ¹¹¹In-DOTA-MSH_oct is excreted intact 4 h after injection, indicating good in vivo stability. Conclusion: ¹¹¹In-DOTA-MSH_oct exhibits more favorable overall performance than does ¹¹¹In-DOTA-NDP-MSH in murine models of primary and metastatic melanoma, making it a promising melanoma imaging agent.

Key Words: melanoma imaging • melanocortin type 1 receptor • -melanocyte–stimulating hormone • DOTA • scintigraphy

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