Development of radioiodine labeled acetaminophen for specific, high-contrast imaging of malignant melanoma

Wen Jing Zhu; Masato Kobayashi; Kohei Yamada; Kodai Nishi; Kotaro Takahashi; Asuka Mizutani; Ryuichi Nishii; Leo G Flores 2nd; Naoto Shikano; Munetaka Kunishima; Keiichi Kawai

doi:10.1016/j.nucmedbio.2017.12.008

Development of radioiodine labeled acetaminophen for specific, high-contrast imaging of malignant melanoma

Nucl Med Biol. 2018 Apr:59:16-21. doi: 10.1016/j.nucmedbio.2017.12.008. Epub 2018 Jan 3.

Authors

Affiliations

¹ Department of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
² Wellness Promotion Science Center, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan. Electronic address: kobayasi@mhs.mp.kanazawa-u.ac.jp.
³ Department of Pharmaceutical Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
⁴ Department of Radioisotope Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
⁵ Graduate School of Medicine, Division of Health Science, Osaka University, Osaka, Japan; Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan.
⁶ Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
⁷ Department of Cancer Systems Imaging, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Radiological Sciences, Ibaraki Prefectural Sciences of Health Sciences, Ibaraki, Japan.
⁹ Department of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan; Biomedical Imaging Research Center, University of Fukui, Fukui, Japan.

PMID: 29413752
DOI: 10.1016/j.nucmedbio.2017.12.008

Abstract

Introduction: Due to its poor prognosis, specific imaging for early detection of malignant melanoma is strongly desired. Although radioiodine labeled 4-hydroxyphenylcysteamine, which we previously developed, has good affinity for tyrosinase, an enzyme in the melanin metabolic pathway, image contrast of the melanoma:organ ratios is not sufficiently high for detection of primary melanoma and metastases at early injection times. In this study, we developed radioiodine labeled acetaminophen (I-AP) for specific, high-contrast imaging of malignant melanoma.

Methods: Radioiodine-125-labeled AP (¹²⁵I-AP) was prepared using the chloramine-T method under no carrier-added conditions. Accumulation of radioactivity and the mechanism were evaluated in vitro using B16 melanoma cells incubated with ¹²⁵I-AP or ¹⁴C(U)-labeled AP (¹⁴C-AP) with and without l-tyrosine as a substrate of tyrosinase, phenylthiourea as an inhibitor of tyrosinase, and thymidine as an inhibitor of DNA polymerase. The biological distribution of radioactivity in B16 melanoma-bearing mice was evaluated to determine the accumulation of ¹²⁵I-AP. The stability of ¹²⁵I-AP over time was evaluated in mice.

Results: The labeling efficiency and radiochemical purity of ¹²⁵I-AP were >80% and 95%, respectively. Accumulation of ¹²⁵I-AP was higher than that of ¹⁴C-AP at 60 min of incubation in vitro. The affinity of ¹⁴C-AP for tyrosinase and DNA polymerase was higher than that of ¹²⁵I-AP, whereas the V_max of ¹²⁵I-AP was higher than that of ¹⁴C-AP. ¹²⁵I-AP showed the highest accumulation in the gall bladder, and clearance from the blood and kidney was rapid. Melanoma:muscle and melanoma:normal skin ratios of ¹²⁵I-AP for imaging contrast were the highest at 15 min after injection, whereas the melanoma:blood and melanoma:bone ratios gradually increased over time. ¹²⁵I-AP remained stable for 60 min after injection in mice.

Conclusions: ¹²⁵I-AP has affinity for tyrosinase and high image contrast at early time points after injection. Therefore, ¹²³I-AP imaging has great potential for specific, high-contrast detection of malignant melanoma. ADVANCES IN KNOWLEDGE: ¹²³I-AP will provide specific, high-contrast imaging for malignant melanoma at early injection times. IMPLICATIONS FOR PATIENT CARE: ¹²³I-AP has good potential for the diagnosis of malignant melanoma compared with ¹²³I-labeled 4-hydroxyphenylcysteamine, which we previously developed.

Keywords: Acetaminophen; Malignant melanoma; Radioiodine; SPECT imaging; Tyrosinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetaminophen / chemistry*
Acetaminophen / pharmacokinetics
Animals
Iodine Radioisotopes*
Isotope Labeling
Male
Melanoma, Experimental / diagnostic imaging*
Melanoma, Experimental / metabolism
Mice
Molecular Imaging / methods*
Tissue Distribution

Substances

Iodine Radioisotopes
Acetaminophen
Iodine-125