Introduction: A specific diagnosis for melanoma is strongly desired because malignant melanoma has poor prognosis. In a previous study, although radioiodine-125-labeled 4-hydroxyphenyl-L-cysteine ((125)I-L-PC) was found to have good substrate affinity for tyrosinase enzyme in the melanin metabolic pathway, (123/131)I-L-PC had insufficient substrate affinity for tyrosinase to diagnose melanoma. In this study, we synthesized 4-hydroxyphenylcysteamine (4-PCA) and developed a novel radioiodine-125-labeled 4-hydroxyphenylcysteamine ((125)I-PCA) to increase affinity for the melanin biosynthesis pathway.
Methods: 4-PCA was separated with 2-hydroxyphenylcysteamine (2-PCA), which is an isomer of 4-PCA, and was examined using melting point, proton nuclear magnetic resonance, mass spectrometry and elemental analysis. (125)I-PCA was prepared using the chloramine-T method under no-carrier added conditions. We performed biodistribution experiments using B16 melanoma-bearing mice using (125)I-PCA, (125)I-L-PC, (125)I-α-methyl-L-tyrosine, (123)I-m-iodobenzylguanidine and (67)Ga-citrate. In vitro assay was performed with B16 melanoma cells, and affinity for tyrosinase, DNA polymerase and amino acid transport was evaluated using phenylthiourea, thymidine, ouabine and L-tyrosine inhibitor. In addition, partition coefficients of (125)I-PCA were evaluated.
Results: In the synthesis of 4-PCA, analysis values did not differ between calculated and reported values, and 4-PCA was separated from 2-PCA at high purity. In biodistribution experiments, (125)I-PCA was accumulated and retained in B16 melanoma cells when compared with (125)I-L-PC. (125)I-PCA showed the highest values at 60 min after radiotracer injection in melanoma-to-muscle ratios, melanoma-to-blood ratios and melanoma-to-skin ratios. Accumulation of (125)I-PCA was significantly inhibited by phenylthiourea and thymidine. Partition coefficients of (125)I-PCA were lower than those of N-isopropyl-p-[(123)I]iodoamphetamine and were not significantly different from (125)I-L-PC.
Conclusions: (125)I-PCA is a better substrate for tyrosinase and DNA polymerase and has higher uptake and longer retention in B16 melanoma cells when compared with (125)I-L-PC. Therefore, (123/131)I-PCA has good potential for diagnosis for malignant melanoma.
Advance in knowledge: (125)I-PCA will be a specific diagnosis tool for malignant melanoma.
Implications for patient care: (123/131)I-PCA has good potential for the diagnosis of malignant melanoma when compared with other SPECT tracers, as well as anti-melanoma chemotherapeutic drugs.
Keywords: 4-hydroxyphenylcysteamine; Malignant melanoma; Radioiodine; SPECT imaging; Tyrosinase.
Copyright © 2015. Published by Elsevier Inc.