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

¹ Laboratory of Endocrinology, Department of Research, University Hospital and University Children’s Hospital, Basel, Switzerland
² Department of Diagnostic and Therapeutic Radiology, German Cancer Research Center, Heidelberg, Germany

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 -melanocyte-stimulating hormone (-MSH; receptor name, melanocortin type 1 receptor [MC1R]), radiolabeled -MSH analogs are potential candidates for melanoma diagnosis. The aim of this study was to develop a positron emitter-labeled -MSH analog suitable for PET imaging of melanoma metastases. Methods: A short linear -MSH analog, [Nle⁴,Asp⁵,D-Phe⁷]--MSH_4–11 (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--MSH analog, DOTA-MSH_oct ([DOTA-ßAla³,Nle⁴,Asp⁵,D-Phe⁷,Lys¹⁰]--MSH_3–10), the major modification lies in the conjugation of DOTA to the C-terminal end of the peptide via the -amino group of Lys¹¹, as opposed to the N-terminal -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-MSH_oct. In B16F1 melanoma-bearing mice, both ¹¹¹In-DOTA-NAPamide and ⁶⁷Ga-DOTA-NAPamide behaved more favorably than ¹¹¹In-DOTA-MSH_oct. 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-MSH_oct. 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-MSH_oct 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.

Key Words: melanoma imaging • -melanocyte-stimulating hormone • 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid • ⁶⁷Ga/⁶⁸Ga • PET

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