Synthesis of Analogue of α-MSH for Targeting of Melanocortin Receptors - Copper-Free Click Chemistry Approach

摘要

Melanoma is a fonii of cancer that starts in melanocytes cells that make pigment melanin. According to the National Cancer Institute, there were 68,130 of new cases of melanoma and 8,650 deaths in the United States in 2010. While melanoma contributes only five percent of all skin cancer, it results in more than fifty percent of deaths related to skin cancer. Also, long-term survival in patients with metastatic disease is only five percent. That is why the early diagnosis of melanoma cancer is critically important for the improvement of survival rate. Melanoma alters expression of cell surface proteins, including adhesion proteins and receptors. For example, melanocortin 1 receptor (MCIR) is one of the five G-protein coupled receptors (MC1R-MC5R) and was found to be overexpressed in more than eighty percent of melanoma tumor samples from patients with metastatic lesions. Thus, MCIR has been investigated as a target for receptor based melanoma diagnosis, as well as monitoring of therapeutic responses, resulting in a discovery of a number of highly potent ligands [1]. For example, [Nle~4, D-Phe~7]- α-MSH labeled with ~(99)mTc-CGCG was shown to bind to melanomas with high avidity. However, this probe also binds to MC3R-MC5Rs, which are found in the kidney and brain. Here, we report the preparation and modification of a peptide ligand that is known to bind selectively to MCIR. We also used an azide-alkyne cycloaddifion reacfion using copper-free click chemistry that can allow us to modify this peptide with a range of different tag-probes for fluorescent and other types of imaging.