Abstract
The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide (45)Ti 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 (45)Ti((IV)), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the (45)Ti 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 [(45)Ti][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 (45)Ti((IV)), provides a foundation for advancing the application of (45)Ti in nuclear medicine, and reveals that Ent can be repurposed as a (45)Ti-complexing cargo for targeted nuclear imaging applications.