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


CONCLUSIONS
(125)I-PCA will be a specific diagnosis tool for malignant melanoma.


CONCLUSIONS
(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.
Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan. Electronic address: kobayasi@mhs.mp.kanazawa-u.ac.jp.
Masato
M
Kobayashi
Department of Radiology, Faculty of Medicine University of Miyazaki, Miyazaki, Japan. Electronic address: rnishii@med.miyazaki-u.ac.jp.
Ryuichi
R
Nishii
Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan.
Naoto
N
Shikano
Department of Cancer Systems Imaging, UT-M.D. Anderson Cancer Center, Houston, TX, USA.
Leo G
LG
Flores
School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
Asuka
A
Mizutani
Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan.
Kazuhiro
K
Ogai
Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan.
Jyunko
J
Sugama
Department of Radiology, Faculty of Medicine University of Miyazaki, Miyazaki, Japan.
Shigeki
S
Nagamachi
Department of Cancer Systems Imaging, UT-M.D. Anderson Cancer Center, Houston, TX, USA.
Keiichi
K
Kawai
D000818:Animals; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D008297:Male; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging*; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000737:chemistry
C481866:3-iodo-4-hydroxyphenylcysteine; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D014443:Tyrosine; D014442:Monophenol Monooxygenase; D003545:Cysteine
4-hydroxyphenylcysteamine; Malignant melanoma; Radioiodine; SPECT imaging; Tyrosinase