Development of radioiodine-labeled 4-hydroxyphenylcysteamine for specific diagnosis of malignant melanoma

作者：Kobayashi Masato^*; Nishii Ryuichi; Shikano Naoto; Flores Leo G; Mizutani Asuka; Ogai Kazuhiro; Sugama Jyunko; Nagamachi Shigeki; Kawai Keiichi

来源：Nuclear Medicine and Biology, 2015, 42(6): 536-540.

DOI：10.1016/j.nucmedbio.2015.02.004

• Malignant melanoma
• Radioiodine
• SPECT imaging
• Tyrosinase
• 4-hydroxyphenylcysteamine

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 (I-125-L-PC) was found to have good substrate affinity for tyrosinase enzyme in the melanin metabolic pathway, 1231131 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 (I-125-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. I-125-PCA was prepared using the chloramine-T method under no-carrier added conditions. We performed biodistribution experiments using B16 melanoma-bearing mice using I-125-PCA, I-125-L-pc, I-125-alpha-methyl-L-tyrosine, I-123-m-iodobenzylguanidine and Ga-67-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 I-125-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, I-125-PCA was accumulated and retained in B16 melanoma cells when compared with 125I-L-PC. I-125-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 I-125-PCA was significantly inhibited by phenylthiourea and thymidine. Partition coefficients of I-125-PCA were lower than those of N-isopropyl-p-[I-123]iodoamphetamine and were not significantly different from 125I-L-PC.
Conclusions: I-125-PCA is a better substrate for tyrosinase and DNA polymerase and has higher uptake and longer retention in B16 melanoma cells when compared with 125I-L-PC. Therefore, I-123/131-PCA has good potential for diagnosis for malignant melanoma.
Advance in Knowledge: I-125-PCA will be a specific diagnosis tool for malignant melanoma.
Implications for Patient Care: I-123/131-PCA has good potential for the diagnosis of malignant melanoma when compared with other SPECT tracers, as well as anti-melanoma chemotherapeutic drugs.

• 出版日期2015-6
• 单位河北医科大学