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Journal of Nuclear Medicine Vol. 43 No. 12 1699-1706
© 2002 by Society of Nuclear Medicine

Basic Science Investigations

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

Sylvie Froidevaux, PhD, Martine Calame-Christe, PhD, Heidi Tanner, Lazar Sumanovski, BSc and Alex N. Eberle, PhD

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 {alpha}-melanocyte–stimulating hormone ({alpha}-MSH; receptor name: melanocortin type 1 receptor, or MC1R), radiolabeled {alpha}-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a melanoma-selective radiolabeled {alpha}-MSH analog suitable for melanoma diagnosis. Methods: The very potent {alpha}-MSH analog [Nle4, D-Phe7]-{alpha}-MSH (NDP-MSH) and a newly designed {alpha}-MSH octapeptide analog, [ßAla3, Nle4, Asp5, D-Phe7, Lys10]-{alpha}-MSH3–10 (MSHoct), 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-MSHoct 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-MSHoct 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-MSHoct 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-MSHoct 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-MSHoct). Lung and liver melanoma metastases could easily be visualized on tissue section autoradiographs after injection of 111In-DOTA-MSHoct. Radio–reversed-phase high-performance liquid chromatography analysis of urine samples revealed that most 111In-DOTA-MSHoct is excreted intact 4 h after injection, indicating good in vivo stability. Conclusion: 111In-DOTA-MSHoct 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 • {alpha}-melanocyte–stimulating hormone • DOTA • scintigraphy




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