Al¹⁸F-labeled á-MSH peptide derivative for early detection of melanoma

Objectives: Early detection plays a role in the management of melanoma patients. While radiolabeled α-melanocyte-stimulating hormone (α-MSH) analogs targeting the melanocortin-1 (MC1) receptor such as ⁶⁷Ga/⁶⁴Cu-labeled Gly-Gly-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-CONH₂ (GGNle-cycMSH_hex) have shown promising biodistribution profiles especially, high tumor uptake, the use of ¹⁸F may further improve detectability and availability. However, conventional ¹⁸F-labeling methods for peptide are complicated and low radiochemical yield, and structural modification associated with ¹⁸F-labeling may affect tracer pharmacokinetics. To prepare ¹⁸F-labeled GGNle-cycMSH_hex easily with high radiochemical yield while maintaining tracer structure, we evaluated applicability of Al¹⁸F with chelate. The potential of Al¹⁸F-GGNle-cycMSH_hex for early detection of melanoma was also investigated.

Methods: 1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA)-conjugated GGNle-cycMSH_hex was prepared by Fmoc solid-phase synthesis. Radiolabeled peptide was prepared byincubating NOTA-GGNle-cycMSH_hex with Al¹⁸F at 105°C using microwave for 15 min, followed by RP-HPLC purification. Biodistribution study was conducted on B16/F10 melanoma-bearing mice at 30 min, 1 h, and 3 h after injection. To evaluate potential of Al¹⁸F-GGNle-cycMSH_hex for early detection of melanoma, PET imaging was performed on tumor-bearing mice approx. 1 week after cell inoculation.

Results: Al¹⁸F-NOTA-GGNle-cycMSH_hex was prepared in high radiochemical yield (> 90%) and high radiochemical purity (> 95%) after HPLC purification. Al¹⁸F-NOTA-GGNle-cycMSH_hex showed high accumulation in the tumor at 30 min and 1 h after injection (6.69 ± 1.49 and 7.70 ± 1.71 %ID/g, respectively), then decreased at 3 h post injection (3.74 ± 0.77 %ID/g). Since blood clearance was rapid, the tumor to blood ratio was increased with time (3.46 ± 0.89, 12.67 ± 1.29, and 35.27 ± 9.12 at 30 min, 1 h, and 3 h after injection, respectively). Kidney showed the highest uptake value at 30 min after injection (8.46 ± 3.09 %ID/g) but gradually decreased at 1 h and 3 h (5.52 ± 0.57 %ID/g and 2.39 ± 0.96 %ID/g). This pharmacokinetics was similar tendency with those of ⁶⁷Ga/⁶⁴Cu-labeled GGNle-cycMSH_hex. In the PET imaging, Al¹⁸F-NOTA-GGNle-CycMSH_hex clearly visualized very small tumors (Fig, approx. 5 mm).

Conclusions: We have successfully prepared Al¹⁸F-NOTA-GGNle-CycMSH_hex in a simple and efficient manner. Al¹⁸F-NOTA-GGNle-CycMSH_hex showed high tumor accumulation in melanoma-bearing mice, and clearly visualized very small tumor. These findings suggest that Al¹⁸F-NOTA-GGNle-CycMSH_hex would be a promising PET tracer for melanoma imaging in early stage.

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