F-18-Labeled Cyclized Alpha-Melanocyte-Stimulating Hormone Derivatives For Imaging Human Melanoma Xenograft With Positron Emission Tomography

Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed alpha-melanocyte-stimulating hormone (alpha MSH) derivatives, [Ga-68]Ga-CCZ01048 and [F-18]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. In this study, we aim to evaluate [F-18]CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF3) derivative, [F-18]CCZ01096, for targeting human melanoma xenograft using mu PET imaging. The peptides were synthesized on solid phase using Fmoc chemistry. Radiolabeling was achieved in a one-step F-18-F-19 isotope-exchange reaction. mu PET imaging and biodistribution studies were performed in NSG mice bearing SK-MEL-1 melanoma xenografts. The MC1R density on the SK-MEL-1 cell line was determined to be 972 +/- 154 receptors/cell (n = 4) via saturation assays. Using [F-18]CCZ01064, moderate tumor uptake (3.05 +/- 0.47% ID/g) and image contrast were observed at 2 h post-injection. Molar activity was determined to play a key role. CCZ01096 with two AmBF3 motifs showed comparable sub-nanomolar binding affinity to MC1R and much higher molar activity. This resulted in improved tumor uptake (6.46 +/- 1.42% ID/g) and image contrast (tumor-to-blood and tumor-to-muscle ratios were 30.6 +/- 5.7 and 85.7 +/- 11.3, respectively) at 2 h post-injection. [F-18]CCZ01096 represents a promising alpha MSH-based mu PET imaging agent for human melanoma and warrants further investigation for potential clinical translation.