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.
Keywords:
PET; PSMA; titanium-45.
MeSH terms
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Animals
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Computer Simulation*
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Glutamic Acid / chemistry
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Glutamic Acid / pharmacology
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Humans
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Kallikreins / chemistry
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Kallikreins / pharmacokinetics
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Kallikreins / pharmacology
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Male
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Mice
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Mice, Inbred BALB C
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Neoplasms, Experimental / diagnostic imaging*
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Neoplasms, Experimental / metabolism
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PC-3 Cells
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Positron-Emission Tomography*
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Prostate-Specific Antigen / chemistry
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Prostate-Specific Antigen / pharmacokinetics
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Prostate-Specific Antigen / pharmacology
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Prostatic Neoplasms / diagnostic imaging*
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Prostatic Neoplasms / metabolism
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Pyridones / chemistry
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Pyridones / pharmacokinetics
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Pyridones / pharmacology
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Radioactive Tracers
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Radiopharmaceuticals* / chemical synthesis
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Radiopharmaceuticals* / chemistry
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Radiopharmaceuticals* / pharmacokinetics
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Radiopharmaceuticals* / pharmacology
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Titanium* / chemistry
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Titanium* / pharmacokinetics
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Titanium* / pharmacology
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Urea / chemistry
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Urea / pharmacology
Substances
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Pyridones
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Radioactive Tracers
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Radiopharmaceuticals
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chelidamic acid
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Glutamic Acid
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Urea
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Titanium
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KLK3 protein, human
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Kallikreins
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Prostate-Specific Antigen