A Gallium-Labeled DOTA-α-Melanocyte- Stimulating Hormone Analog for PET Imaging of Melanoma Metastases

Journal of Nuclear Medicine

Jochen Schuhmacher¹  Alex N. Eberle¹  Heidi Tanner¹  Rainer Saffrich¹  Martine Calame-Christe¹  Markus Henze¹  Sylvie Froidevaux¹ 

关键词: melanoma imaging;    α-melanocyte-stimulating hormone;    1;    4;    7;    10-tetraazacyclododecane-1;    4;    7;    10-tetraacetic acid;    ⁶⁷Ga/⁶⁸Ga;    PET;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Although 18F-FDG PET is widely used for metastatic melanoma diagnosis, it is less accurate than desirable, particularly for small foci. Since both melanotic and amelanotic melanomas overexpress receptors for α-melanocyte-stimulating hormone (α-MSH; receptor name, melanocortin type 1 receptor [MC1R]), radiolabeled α-MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a positron emitter-labeled α-MSH analog suitable for PET imaging of melanoma metastases. Methods: A short linear α-MSH analog, [Nle4,Asp5,d-Phe7]-α-MSH4–11 (NAPamide), was newly designed and conjugated to the metal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to enable radiometal incorporation. Compared with our previously reported DOTA-α-MSH analog, DOTA-MSHoct ([DOTA-βAla3,Nle4,Asp5,d-Phe7,Lys10]-α-MSH3–10), the major modification lies in the conjugation of DOTA to the C-terminal end of the peptide via the ε-amino group of Lys11, as opposed to the N-terminal α-amino group. After labeling with 111In, 67Ga, and the short-lived positron emitter 68Ga, DOTA-NAPamide was characterized in vitro and in vivo using the mouse melanoma B16F1cell line. Results: DOTA-NAPamide exhibited an almost 7-fold higher MC1R binding potency as compared with DOTA-MSHoct. In B16F1 melanoma-bearing mice, both 111In-DOTA-NAPamide and 67Ga-DOTA-NAPamide behaved more favorably than 111In-DOTA-MSHoct. Both radiopeptides exhibited higher tumor and lower kidney uptake leading to tumor-to-kidney ratios of the 4- to 48-h area under the curve that were 4.6 times (111In) and 7.5 times (67Ga) greater than that obtained with 111In-DOTA-MSHoct. In addition, the 4-h kidney uptake of 67Ga-DOTA-NAPamide could be reduced by 64% by coinjection of 15 mg l-lysine, without affecting tumor uptake. Skin primary melanoma as well as lung and liver melanoma metastases could be easily visualized on tissue section autoradiographs after systemic injection of 67Ga-DOTA-NAPamide. The melanoma selectivity of DOTA-NAPamide was confirmed by PET imaging studies using 68Ga-DOTA-NAPamide. Tumor uptake was found to be highest when the smallest amount of peptide was administered. Conclusion: DOTA-NAPamide labeled with either 111In or 67Ga/68Ga is in every way superior to 111In-DOTA-MSHoct in murine models of primary and metastatic melanoma, which makes it a promising agent for melanoma targeting. High-contrast images obtained in PET studies with an experimental tumor model 1 h after injection augurs well for its clinical potential as an imaging tool.

【 授权许可】

Unknown