Melanoma Imaging Using F-18-Labeled alpha-Melanocyte-Stimulating Hormone Derivatives with Positron Emission Tomography

作者：Zhang Chengcheng; Zhang Zhengxing; Lin Kuo Shyan; Lau Joseph; Zeisler Jutta; Colpo Nadine; Perrin David M; Benard Francois^*

来源：Molecular Pharmaceutics, 2018, 15(6): 2116-2122.

DOI：10.1021/acs.molpharmaceut.7b01113

• Melanocortin 1 receptor
• Melanoma
• alpha-melanocyte-stimulating hormone
• PET imaging
• F-18
• Trifluoroborate

Melanocortin 1 receptor (MC1R) is specifically expressed in the majority of melanomas, a leading cause of death related to skin cancers. Accurate staging and early detection is crucial in managing melanoma. Based on the alpha-melanocyte-stimulating hormone (alpha MSH) sequence, MC1R-targeted peptides have been studied for melanoma imaging, predominately for use with single-photon emission computed tomography, with few attempts made for positron emission tomography (PET). F-18 is a commonly used PET isotope due to readily available cyclotron production, pure positron emission, and a favorable half-life (109.8 min). In this study, we aim to design and evaluate alpha MSH derivatives that enable radiolabeling with F-18 for PET imaging of melanoma. We synthesized three imaging probes based on the structure of Nle(4-)cylo[Asp(5)-His-D-Phe(7)-Arg-Trp-Lys(10)]-NH2 (Nle-CycMSH(hex)), with a Pip linker (CCZ01064), an Acp linker (CCZ01070), or an Aoc linker (CCZ01071). F-18 labeling was enabled by an ammoniomethyl-trifluoroborate (AmBF3) moiety. In vitro competition binding assays showed subnanomolar inhibition constant (K-i) values for all three peptides. The F-18 radiolabeling was performed via a one-step F-18-F-19 isotope exchange reaction that resulted in high radiochemical purity (>95%) and good molar activity (specific activity) ranging from 40.7 to 66.6 MBq/nmol. All three F-18-labeled peptides produced excellent tumor visualization with PET imaging in C57BL/6J mice bearing B16-F10 tumors. The tumor uptake was 7.80 +/- 1.77, 5.27 +/- 2.38, and 5.46 +/- 2.64% injected dose per gram of tissue (%ID/g) for [F-18]CCZ01064, [F-18]CCZ01070, and [F-18]CCZ01071 at 1 h post-injection (p.i.), respectively. Minimal background activity was observed except for kidneys at 4.99 +/- 0.20, 4.42 +/- 0.54, and 13.55 +/- 2.84% ID/g, respectively. The best candidate [F-18]CCZ01064 was further evaluated at 2 h p.i., which showed increased tumor uptake at 11.96 +/- 2.31% ID/g and further reduced normal tissue uptake. Moreover, a blocking study was performed for CCZ01064 at 1 h p.i., where tumor uptake was significantly reduced to 1.97 +/- 0.60% ID/g, suggesting the tumor uptake was receptor mediated. In conclusion, [F-18]CCZ01064 showed high tumor uptake, low normal tissue uptake, and fast clearance and is therefore a suitable and promising candidate for PET imaging of melanoma.

• 出版日期2018-6