Design, Synthesis, Computational, and Preclinical Evaluation of ^natTi/⁴⁵Ti-Labeled Urea-Based Glutamate PSMA Ligand

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide ⁴⁵Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid-liquid extraction (LLE) in flow-based recovery and the purification of ⁴⁵Ti, computer-aided design, and the synthesis of a salan-^natTi/⁴⁵Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.