Design, synthesis, computational, and preclinical evaluation of Natti/45Ti-labeled urea-based glutamate PSMA ligand

Kristina Søborg Pedersen, Christina Baun, Karin Michaelsen Nielsen, Helge Thisgaard, Andreas Ingemann Jensen, Fedor Zhuravlev*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

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.

Original languageEnglish
Article number1104
JournalMolecules
Volume25
Issue number5
Number of pages19
ISSN1420-3049
DOIs
Publication statusPublished - 2. Mar 2020

Keywords

  • PET
  • PSMA
  • Titanium-45

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