Abstract
Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed α-melanocyte-stimulating hormone (αMSH) derivatives, [68Ga]Ga-CCZ01048 and [18F]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. In this study, we aim to evaluate [18F]CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF3) derivative, [18F]CCZ01096, for targeting human melanoma xenograft using μPET imaging. The peptides were synthesized on solid phase using Fmoc chemistry. Radiolabeling was achieved in a one-step 18F-19F isotope-exchange reaction. μPET 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 [18F]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. [18F]CCZ01096 represents a promising αMSH-based μPET imaging agent for human melanoma and warrants further investigation for potential clinical translation.
Highlights
Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease
We recently reviewed the development of α-melanocyte-stimulating hormone (αMSH) derivatives for melanoma imaging targeting melanocortin 1 receptor (MC1R) with μPET and μSPECT, and summarized the biodistribution characteristics of 88 radiolabeled αMSH derivatives evaluated in mice bearing mouse melanoma[17]
The use of mouse melanoma models facilitated the development of a large number of αMSH derivatives for μPET and μSPECT imaging[17]
Summary
Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed α-melanocyte-stimulating hormone (αMSH) derivatives, [68Ga]Ga-CCZ01048 and [18F]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. The most popular molecular targets for μPET imaging of melanoma and their respective ligands in preclinical studies are: (1) melanocortin 1 receptor (MC1R) and α-melanocyte-stimulating hormone (αMSH) peptide derivatives[9,10]; (2) melanin and benzamide-bearing pharmacophores[11,12]; (3) integrin αvβ[3] and RGD derivatives[13,14]; and (4) integrin α4β1 ( known as very late antigen-4, VLA-4) and peptidomimetic ligand LLP2A derivatives[15,16]. The aim of this study was to evaluate the potential of our previously reported CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF3) derivative, CCZ01096 (Fig. 1c), for detecting human melanoma xenografts with μPET in a preclinical mouse model
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