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

Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry
Kristina Søborg PedersenFedor Zhuravlev

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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Citations

Dec 2, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Di XiaoJunbo Zhang
Aug 8, 2021·Journal of Inorganic Biochemistry·Rosario SerranoMaria Jose Ruiz

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Methods Mentioned

BETA
column chromatography

Software Mentioned

SRIM ( Stopping and Range of Ions in Matter )
CosmothermX
OSEM3D
Schrodinger
Turbomole

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