"Off-Label Use" of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti^(IV)

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide Ti-45 for radiopharmaceutical applications. Herein, we evaluate the Ti-(IV)-coordination chemistry of four catechol-based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN-CAM readily form mononuclear Ti-(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN-CAM form mononuclear complexes with the short-lived, positron-emitting radionuclide Ti-45((IV)), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in na & iuml;ve mice. These features guide efforts to target the Ti-45 isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent-DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [Ti-45][Ti(Ent-DUPA)](2-) complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8 +/- 5 %, n=5), and low off-target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with Ti-45((IV)), provides a foundation for advancing the application of Ti-45 in nuclear medicine, and reveals that Ent can be repurposed as a Ti-45-complexing cargo for targeted nuclear imaging applications.