Radioiodination of Two Carborane-Based Dual Cyclooxygenase-2/5-Lipoxygenase Inhibitors and Their In Vitro and In Vivo...

Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) are key enzymes in prostanoid and leukotriene signaling and are overexpressed in various cancers, correlating with malignancy and metastasis. This renders them promising molecular targets for radiotracer development. In this study, isomeric closo-dicarbadodecaborane(12)-based dual COX-2/5-LO inhibitors (1 and 2) served as scaffolds for iodine-123-labeling. Iodinated derivatives 3 and 4 inhibited 5-LO more potently than COX-2 in vitro (IC₅₀ 0.62 µM and 41.3 µM (3); 0.54 µM and 67.7 µM (4)). Radioiodination yielded 39%-71% of [¹²³I]3 and [¹²³I]4; and the formulations were stabilized with antioxidants. Cellular uptake of [¹²³I]3 and [¹²³I]4 was evaluated in human cells with distinct COX-2 and 5-LO expression: U87 glioblastoma, HT-29 colorectal carcinoma cells, THP-1 monocytes (MC) and macrophages. Consistent with the observed inhibitory potency, the uptake of the radiotracers proved to be independent of COX-2 expression. In contrast, it was influenced by 5-LO expression in tumor but not inflammatory cells. Single-photon emission computed tomography imaging in tumor xenograft mouse models revealed no tumor retention of [¹²³I]3 and [¹²³I]4 due to rapid metabolism via radiodeiodination. Despite successful radiosynthesis and in vitro evaluation of iodine-123-labeled COX-2/5-LO inhibitors, improved inhibitory activity and stability are required for development of suitable radiotracers.