A comprehensive review of 11C-, 18F-, and 123/124/125I-labeled radiotracers targeting cyclooxygenase-2 over the past two decades.

Cyclooxygenase-2 (COX-2), an inducible enzyme pivotal to prostaglandin biosynthesis from arachidonic acid, is aberrantly upregulated in inflammatory pathologies, neurodegenerative disorders, and malignancies. Non-invasive real-time quantification of COX-2 expression in vivo via nuclear imaging method (positron emission tomography (PET) and single-photon emission computed tomography (SPECT)) has an important significance. It not only enables disease stratification and prognostic assessment but also clarifies COX-2's pathophysiological roles, thereby guiding therapeutic decision-making. As COX-2 inhibitors are widely used to manage acute/chronic inflammation and pain, their radiolabeling has facilitated the development of targeted molecular probes for COX-2 imaging. This review systematically categorizes radiotracers derived from structurally modified COX-2 inhibitors, with a focus on 11C-, 18F-, and 123/124/125I-labeled compounds, and analyses their synthesis as well as in vitro and in vivo properties in detail. Despite these advances, clinical translation still faces considerable difficulties. Ongoing efforts in structural optimization, combined with the development of advanced COX-2-expressing transgenic models, are expected to address these limitations. Future radiotracers may ultimately enable reliable COX-2 quantification via nuclear imaging, thus bridging a critical gap in precision medicine.