Mapping Arginase Expression with ¹⁸F-Fluorinated Late-Generation Arginase Inhibitors Derived from Quaternary α-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 evaluation of 2 radiolabeled arginase inhibitors, ¹⁸F-FMARS and ¹⁸F-FBMARS, developed from α-substituted-2-amino-6-boronohexanoic acid derivatives. <b>Methods:</b> 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. <b>Results:</b>¹⁸F-fluorinated compounds were obtained with radiochemical yields of up to 5% (decay-corrected) and an average molar activity of 53 GBq⋅μmol^-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). <b>Conclusion:</b> 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 arginase-inhibited PC3 xenografted mice. These results encourage further research to examine the suitability of ¹⁸F-FBMARS for selecting patients for treatments with arginase inhibitors.