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Paper | Special issue | Vol 101, No. 2, 2020, pp.559-579
Published online, 2nd October, 2019
DOI: 10.3987/COM-19-S(F)47
Development of Near-Infrared Fluorescent Probes with Large Stokes Shifts for Non-Invasive Imaging of Tumor Hypoxia

Kensuke Okuda, Bahaa G. M. Youssif, Ryosuke Sakai, Takahiro Ueno, Takayuki Sakai, Tetsuya Kadonosono, Yasuyuki Okabe, Ola I. Abdel Razek Salem, Alaa M. Hayallah, Mostafa A. Hussein, Shinae Kizaka-Kondoh, and Hideko Nagasawa*

*Laboratory of Pharmaceutical & Medicinal Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan

Abstract

A series of near-infrared (NIR) fluorochromes with large Stokes shifts was designed, synthesized, and evaluated for application in non-invasive imaging of tumor hypoxia. Each NIR fluorescent hypoxia probe comprised a tricarbocyanine dye and a 2-nitroimidazole-containing moiety as a hypoxia marker that binds to cellular nucleophiles via bioreductive activation under hypoxic conditions. Nucleophilic displacement of the amino-nucleophilic linker moiety of heptamethine cyanine dyes having a 2-chloro-1-cyclohexenyl ring and a 2-nitroimidazole moiety yielded various fluorochromes with different hydrophilicity. These exhibited long emission wavelengths (747–758 nm) with large Stokes shifts (111–125 nm) and high quantum yield (0.04–0.34). GPU-210, 297, and 316 showed significantly higher levels of fluorescence under hypoxic than under normoxic conditions on treating SUIT-2/HRE-Luc pancreatic cancer cells. Among these, only GPU-316 showed significant fluorescence intensity in tumor tissue in in vivo fluorescence imaging of mouse xenograft models.