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

Journal of Nuclear Medicine

Alex N. Eberle¹  Heidi Tanner¹  Martine Calame-Christe¹  Sylvie Froidevaux¹ 

关键词: melanoma imaging;    melanocortin type 1 receptor;    α-melanocyte-stimulating hormone;    DOTA;    scintigraphy;    internal radiotherapy;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Radiolabeled analogs of α-melanocyte-stimulating hormone (α-MSH) are potential candidates for the diagnosis and therapy of melanoma metastases. After our recent observation that a linear octapeptide α-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)]-α-MSH4–11 (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-α-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 ε-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 ε-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-α-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-α-MSH analogs and other radiopeptides.

【 授权许可】

Unknown