Tyrosinase-Activated MRI and PET Probes for Selective Melanoma Imaging

Melanoma is one of the most aggressive forms of skin cancer. Accurate and early diagnosis of melanoma is crucial for improving patient outcomes. This study develops two TYR-activatable molecular probes, Mn-TyrEDTA and Al-¹⁸F-TyrEDTA, for the selective detection of melanoma <i>in vivo</i>. <i>In vitro</i> studies reveal that Mn-TyrEDTA exhibits TYR activity-dependent relaxivity enhancement, undergoing TYR-mediated oxidative polymerization, resulting in the formation of paramagnetic oligomers. UV-vis analysis supports this mechanism, showing time- and TYR concentration-dependent increases in broad band absorbance in the UV-vis region, specifically around 475 nm, due to the formation of <i>o</i>-quinone intermediates and melanin-like oligomers. HPLC analysis further confirmed the presence of polar oligomeric products in Mn-TyrEDTA solutions incubated with TYR/O₂. MRI studies demonstrate Mn-TyrEDTA's selective retention and signal enhancement in TYR-expressing melanoma tissues. Furthermore, PET imaging with Al-¹⁸F-TyrEDTA conducted using a dual-xenograft mouse model reveals significantly higher uptake and retention of Al-¹⁸F-TyrEDTA in TYR-expressing melanoma compared to TYR-negative tumors. This selective retention could be attributed to a TYR-mediated proximity labeling mechanism, where highly reactive quinones form covalent bonds with nearby tumor proteins. In summary, our findings establish Mn-TyrEDTA and Al-¹⁸F-TyrEDTA as promising TYR-activatable imaging probes, offering a novel strategy for the early diagnosis and prognosis of melanoma.