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

Abstract

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.

• Authors: Masato Kobayashi, Ryuichi Nishii, Naoto Shikano, Leo G Flores 2nd, Asuka Mizutani, Kazuhiro Ogai, Jyunko Sugama, Shigeki Nagamachi, Keiichi Kawai
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 42 Issue 6 Pg. 536-40 (Jun 2015) ISSN: 1872-9614 [Electronic] United States
• PMID: 25744361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Inc.

Chemical References

• 3-iodo-4-hydroxyphenylcysteine
• Iodine Radioisotopes
• Radiopharmaceuticals
• Tyrosine
• Monophenol Monooxygenase
• Cysteine

Topics

• Animals
• Cysteine (analogs & derivatives, chemistry)
• Iodine Radioisotopes (pharmacokinetics)
• Male
• Melanoma, Experimental (diagnostic imaging)
• Mice
• Mice, Inbred C57BL
• Monophenol Monooxygenase (chemistry)
• Radiopharmaceuticals (chemical synthesis, pharmacokinetics)
• Tissue Distribution
• Tomography, Emission-Computed, Single-Photon (methods)
• Tumor Cells, Cultured
• Tyrosine (chemistry)