Mapping Arginase Expression with 18F-Fluorinated Late-Generation Arginase Inhibitors Derived from Quaternary a-Amino Acids

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 evaluationof 2 radiolabeled arginase inhibitors, 18F-FMARS and 18F-FBMARS, developed from a-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: 18F-fluorinated compounds were obtained with radiochemical yields of up to 5%(decay-corrected) and an averagemolar activity of 53GBq_lmol21. Cell and lung section experiments indicated specific binding that was blocked up to 75% after pretreatment with arginase inhibitors. Smallanimal PET studies indicated fast clearance of the radiotracers (7.3 6 0.6 min), arginase-mediated uptake, and a selective tumor accumulation (SUV, 3.0 6 0.7). Conclusion: The new 18F-fluorinated arginase inhibitors have the potential to map increased arginase expression related to inflammatory and tumorigenic processes. 18F-FBMARS showed the highest arginase-mediated uptake in PET imaging and a significant difference between uptake in control and arginaseinhibited PC3 xenografted mice. These results encourage further researchtoexamine thesuitabilityof 18F-FBMARSfor selectingpatients for treatments with arginase inhibitors.