Investigation and preparation of a TREN-based bifunctional chelator for ⁸⁹Zr

Zirconium-89 (⁸⁹Zr) bears characteristics that are ideal for positron emission tomography (PET) imaging of long-circulating radiopharmaceuticals. However, the most commonly used chelator, deferoxamine (DFO), suffers from limited in vivo stability, leading to leaching of ⁸⁹Zr and subsequent bone accumulation that compromises diagnostic accuracy and dosimetric calculations. Here, we report the first application of the enterobactin-inspired chelator TRENTAM and its bifunctional analogue TRENTAM-COOH for chelating ⁸⁹Zr. Both compounds were synthesized via modular, high-yielding routes and demonstrated efficient radiolabelling with ⁸⁹Zr under mild conditions. In vitro assays showed that [⁸⁹Zr]Zr-TRENTAM and [⁸⁹Zr]Zr-TRENTAM-COOH outperform DFO and TRENHOPO in EDTA and serum stability challenges over 7 days. TRENTAM also exhibited exceptional stability across physiologically relevant pH ranges and resisted transchelation by biologically abundant metal ions. Biodistribution studies in mice demonstrated low nonspecific uptake of [⁸⁹Zr]Zr-TRENTAM. Furthermore, TRENTAM demonstrated negligible cytotoxicity in cells, supporting its biocompatibility. Collectively, these findings establish TRENTAM as a high-affinity, stable, and versatile chelator for ⁸⁹Zr, advancing its potential for use in next-generation targeted PET imaging agents and theranostic applications.