A Reactivity-Based 18F‑Labeled Probe for PET Imaging of Oxidative Stress in Chemotherapy-Induced Cardiotoxicity

• Published in: Molecular pharmaceutics Vol. 19; no. 1; pp. 18 - 25
• Main Authors: Mota, Filipa, Pell, Victoria R, Singh, Nisha, Baark, Friedrich, Waters, Edward, Sadasivam, Pragalath, Southworth, Richard, Yan, Ran
• Format: Journal Article
• Language: English
• Published: American Chemical Society 03.01.2022
• Subjects: cardiotoxicity; fluorine-18; PET imaging; oxidative stress; reactive oxygen species
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00496

Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.