Radiolabeled para-I-Nimesulide: An Unexpected Tracer for Imaging Peripheral Inflammation

Yumi Yamamoto^*Kentaro ImaiYohei SaitoFumihiko Yamamoto

• Tohoku Medical and Pharmaceutical University, Sendai, Japan

In our previous studies, we demonstrated that nimesulide derivatives bearing iodine at the para-position of the phenyl ring exhibit potent inhibitory activity against cyclooxygenase-2 (COX-2). In the present study, we investigated whether radioiodinated derivatives of nimesulide could serve as COX-2 imaging agents for single-photon emission computed tomography (SPECT), with a particular focus on their potential to visualize COX-2 expression in the brain. 125I-labeled derivatives substituted at the para-or meta-positions were synthesized from the corresponding tributyltin precursors with satisfactory radiochemical yields and purities. Biodistribution studies and ex vivo autoradiography in normal mice revealed that [125I]para-I nimesulide exhibited limited brain penetration and did not accurately reflect the distribution of COX-2 in the brain, suggesting it is unsuitable as a brain-targeted imaging agent. In contrast, biodistribution and blocking experiments in a mouse model of inflammation demonstrated selective accumulation of [125I]para-I nimesulide in inflamed regions, which was significantly inhibited by COX-2–selective inhibitors. Moreover, [125I]para-I nimesulide exhibited high radiochemical purity and persistent in vivo stability, but strong plasma albumin binding likely restricted its brain uptake. These findings indicate that while [125I]para-I nimesulide has limited potential for brain-targeted COX-2 imaging, it may serve as a promising tracer for detecting COX-2 expression in peripheral tissues. Importantly, this study also highlighted that the electronic properties of substituents strongly influence metabolic stability, providing valuable insights for the design of future COX-2–targeted molecular imaging agents.