TY - JOUR
T1 - Development of radioiodine-labeled 4-hydroxyphenylcysteamine for specific diagnosis of malignant melanoma
AU - Kobayashi, Masato
AU - Nishii, Ryuichi
AU - Shikano, Naoto
AU - Flores, Leo G.
AU - Mizutani, Asuka
AU - Ogai, Kazuhiro
AU - Sugama, Jyunko
AU - Nagamachi, Shigeki
AU - Kawai, Keiichi
N1 - Funding Information:
Financial support: This study was partly funded by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (24601008, 24659558) and the Nakayama Foundation for Human Science.
Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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 (125I-L-PC) was found to have good substrate affinity for tyrosinase enzyme in the melanin metabolic pathway, 123/131I-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 (125I-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. 125I-PCA was prepared using the chloramine-T method under no-carrier added conditions. We performed biodistribution experiments using B16 melanoma-bearing mice using 125I-PCA, 125I-L-PC, 125I-α-methyl-L-tyrosine, 123I-m-iodobenzylguanidine and 67Ga-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 125I-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, 125I-PCA was accumulated and retained in B16 melanoma cells when compared with 125I-L-PC. 125I-PCA showed the highest values at 60min after radiotracer injection in melanoma-to-muscle ratios, melanoma-to-blood ratios and melanoma-to-skin ratios. Accumulation of 125I-PCA was significantly inhibited by phenylthiourea and thymidine. Partition coefficients of 125I-PCA were lower than those of N-isopropyl-p-[123I]iodoamphetamine and were not significantly different from 125I-L-PC. Conclusions: 125I-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, 123/131I-PCA has good potential for diagnosis for malignant melanoma. Advance in Knowledge: 125I-PCA will be a specific diagnosis tool for malignant melanoma. Implications for Patient Care: 123/131I-PCA has good potential for the diagnosis of malignant melanoma when compared with other SPECT tracers, as well as anti-melanoma chemotherapeutic drugs.
AB - 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 (125I-L-PC) was found to have good substrate affinity for tyrosinase enzyme in the melanin metabolic pathway, 123/131I-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 (125I-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. 125I-PCA was prepared using the chloramine-T method under no-carrier added conditions. We performed biodistribution experiments using B16 melanoma-bearing mice using 125I-PCA, 125I-L-PC, 125I-α-methyl-L-tyrosine, 123I-m-iodobenzylguanidine and 67Ga-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 125I-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, 125I-PCA was accumulated and retained in B16 melanoma cells when compared with 125I-L-PC. 125I-PCA showed the highest values at 60min after radiotracer injection in melanoma-to-muscle ratios, melanoma-to-blood ratios and melanoma-to-skin ratios. Accumulation of 125I-PCA was significantly inhibited by phenylthiourea and thymidine. Partition coefficients of 125I-PCA were lower than those of N-isopropyl-p-[123I]iodoamphetamine and were not significantly different from 125I-L-PC. Conclusions: 125I-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, 123/131I-PCA has good potential for diagnosis for malignant melanoma. Advance in Knowledge: 125I-PCA will be a specific diagnosis tool for malignant melanoma. Implications for Patient Care: 123/131I-PCA has good potential for the diagnosis of malignant melanoma when compared with other SPECT tracers, as well as anti-melanoma chemotherapeutic drugs.
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U2 - 10.1016/j.nucmedbio.2015.02.004
DO - 10.1016/j.nucmedbio.2015.02.004
M3 - Article
C2 - 25744361
AN - SCOPUS:84928824371
VL - 42
SP - 536
EP - 540
JO - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
JF - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
SN - 0969-8051
IS - 6
ER -