1. Mapping Arginase Expression with 18 F-Fluorinated Late-Generation Arginase Inhibitors Derived from Quaternary α-Amino Acids.
- Author
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Clemente GS, Antunes IF, Kurhade S, van den Berg MPM, Sijbesma JWA, van Waarde A, Buijsman RC, Willemsen-Seegers N, Gosens R, Meurs H, Dömling A, and Elsinga PH
- Subjects
- Animals, Mice, Humans, Guinea Pigs, Cell Line, Tumor, Amino Acids chemistry, Amino Acids metabolism, Radiochemistry, Male, Tissue Distribution, Arginase antagonists & inhibitors, Arginase metabolism, Positron-Emission Tomography, Fluorine Radioisotopes, Enzyme Inhibitors pharmacology
- Abstract
Arginase hydrolyzes L-arginine and influences levels of polyamines and nitric oxide. Arginase overexpression is associated with inflammation and tumorigenesis. Thus, radiolabeled arginase inhibitors may be suitable PET tracers for staging arginase-related pathophysiologies. We report the synthesis and evaluation of 2 radiolabeled arginase inhibitors,
18 F-FMARS and18 F-FBMARS, developed from α-substituted-2-amino-6-boronohexanoic acid derivatives. Methods: Arylboronic ester-derived precursors were radiolabeled via copper-mediated fluorodeboronation. Binding assays using arginase-expressing PC3 and LNCaP cells were performed. Autoradiography of lung sections from a guinea pig model of asthma overexpressing arginase and dynamic small-animal PET imaging with PC3-xenografted mice evaluated the radiotracers' specific binding and pharmacokinetics. Results:18 Cell and lung section experiments indicated specific binding that was blocked up to 75% after pretreatment with arginase inhibitors. Small-animal PET studies indicated fast clearance of the radiotracers (7.3 ± 0.6 min), arginase-mediated uptake, and a selective tumor accumulation (SUV, 3.0 ± 0.7).-1 Cell and lung section experiments indicated specific binding that was blocked up to 75% after pretreatment with arginase inhibitors. Small-animal PET studies indicated fast clearance of the radiotracers (7.3 ± 0.6 min), arginase-mediated uptake, and a selective tumor accumulation (SUV, 3.0 ± 0.7). Conclusion: F-fluorinated arginase inhibitors have the potential to map increased arginase expression related to inflammatory and tumorigenic processes.18 F-FBMARS showed the highest arginase-mediated uptake in PET imaging and a significant difference between uptake in control and arginase-inhibited PC3 xenografted mice. These results encourage further research to examine the suitability of18 F-FBMARS for selecting patients for treatments with arginase inhibitors.18 F-FBMARS for selecting patients for treatments with arginase inhibitors., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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