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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.
Highlights
Since its inception in 1975 [1], positron emission tomography (PET) has become one of the most useful and rapidly developing diagnostic modalities in the field of oncology, cardiology, and neurology [2]
The docked structure was further functionalized by attaching the salan-Ti-chelidamic acid (CA) moiety at the benzylic ester linkage forming compound (3), which is referred to as salan-Ti-CA-prostate-specific membrane antigen (PSMA) (3)
A higher radiolabeling yield could be obtained with 4 mM of salan and CA-PSMA at 80 ◦ C by adding pyridine 1/5 (v/v) to the guaiacol/anisole phase, and we found that a reaction time of 15 min was suitable for the formation of [45 Ti]salan-Ti-CA-PSMA ([45 Ti]-3) (Scheme 4)
Summary
Since its inception in 1975 [1], PET has become one of the most useful and rapidly developing diagnostic modalities in the field of oncology, cardiology, and neurology [2]. PET radiopharmaceuticals (tracers) provide functional imaging of disease by precise molecular targeting of the affected tissue. While the radionuclides 68 Ga and 82 Rb still dominate the traditional clinical setting, the use of 64 Cu [5] and 89 Zr [6] is on the rise in university clinics and clinical trials, and a plethora of PET tracers based on more unconventional PET radiometals such as 44 Sc, 45 Ti, 55 Co, and 86 Y are in development [7]. The radionuclide 45 Ti occupies a special place among unconventional PET radiometals, featuring 85% β+ decay, negligible secondary radiation, and low β+ endpoint energy (1.04 MeV), which translates into high spatial resolution as evidenced by sharp Derenzo phantom images [8,9,10]. With its 3.1 h half-life, 45 Ti is well-suited for the radiolabeling of small molecules, Molecules 2020, 25, 1104; doi:10.3390/molecules25051104 www.mdpi.com/journal/molecules
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