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Melanoma Targeting with DOTA--Melanocyte-Stimulating Hormone Analogs: Structural Parameters Affecting Tumor Uptake and Kidney Uptake

¹ Laboratory of Endocrinology, Department of Research, University Hospital and University Children’s Hospital, Basel, Switzerland

Radiolabeled analogs of -melanocyte-stimulating hormone (-MSH) are potential candidates for the diagnosis and therapy of melanoma metastases. After our recent observation that a linear octapeptide -MSH analog incorporating the metal chelator 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) at the C-terminal lysine, [Nle⁴,Asp⁵,D-Phe⁷,Lys¹¹(DOTA)]--MSH_4–11 (DOTA-NAPamide), showed high accumulation in melanomas in a mouse model, low uptake in normal tissues, and moderate uptake in the kidneys, we attempted to identify the structural parameters influencing tumor uptake versus kidney uptake. Methods: We designed a series of novel DOTA--MSH analogs differing from DOTA-NAPamide by small alterations, such as the position of DOTA in the peptide, hydrophobicity, and charge, by modifying the C-terminal Lys¹¹ residue. They were evaluated both for their melanocortin type 1 receptor (MC1R)–binding potency and for their biodistribution by use of the B16F1 melanoma mouse model. Results: When DOTA was shifted to the N terminus of the peptide, a 3-fold increase in kidney retention was obtained. However, when the -amino group of the Lys¹¹ residue was acetylated in addition to the DOTA relocation, kidney uptake returned to the low values obtained with DOTA-NAPamide; this result indicated that neutralization of the -amino group positive charge of the Lys¹¹ residue rather than the position of DOTA accounted for the low kidney retention. Unexpectedly, no further reduction in kidney uptake was obtained by the introduction of 1 or 2 negative charges on Lys¹¹. Melanoma uptake was in accordance with MC1R affinity; the highest values were obtained for peptides bearing carboxy-terminal amidation and positioning of DOTA. Conclusion: The kidney uptake of DOTA--MSH analogs could be considerably reduced, without affecting MC1R affinity, by altering (neutralizing) the charge of the Lys¹¹ residue. Accordingly, the resulting peptides exhibited a high ratio of tumor uptake to kidney uptake that is favorable for diagnostic and therapeutic applications. These structure–activity data may help to improve the performance of DOTA--MSH analogs and other radiopeptides.

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

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