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

doi:10.3390/molecules25051104

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

Department of Health Technology

University of Southern Denmark

Research output: Contribution to journal › Journal article › Research › peer-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 language	English
Article number	1104
Journal	Molecules
Volume	25
Issue number	5
Number of pages	19
ISSN	1420-3049
DOIs	https://doi.org/10.3390/molecules25051104
Publication status	Published - 2020

Keywords

Titanium-45
PSMA
PET

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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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.",

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AU - Thisgaard, Helge

AU - Jensen, Andreas Ingemann

AU - Zhuravlev, Fedor

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