PT  - JOURNAL ARTICLE
AU  - Gonçalo S. Clemente
AU  - Inês F. Antunes
AU  - Santosh Kurhade
AU  - Mariska van den Berg
AU  - Jürgen W.A. Sijbesma
AU  - Aren van Waarde
AU  - Rogier C. Buijsmam
AU  - Nicole Willemsen-Seegers
AU  - Reinoud Gosens
AU  - Herman Meurs
AU  - Alexander Dömling
AU  - Philip H. Elsinga
TI  - Mapping arginase expression with <sup>18</sup>F-fluorinated late-generation arginase inhibitors derived from quaternary α-amino acids
AID  - 10.2967/jnumed.120.255968
DP  - 2021 Mar 01
TA  - Journal of Nuclear Medicine
PG  - jnumed.120.255968
4099  - http://jnm.snmjournals.org/content/early/2021/03/12/jnumed.120.255968.short
4100  - http://jnm.snmjournals.org/content/early/2021/03/12/jnumed.120.255968.full
AB  - Arginase hydrolyzes ʟ-arginine and influences levels of polyamines and nitric oxide (NO•). Arginase overexpression is associated with inflammations and tumorigenesis. Thus, radiolabeled arginase inhibitors may be suitable positron emission tomography (PET) tracers for staging arginase-related pathophysiologies. We report, for the first time, the synthesis and evaluation of radiolabeled arginase inhibitors, 18F-FMARS and 18F-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 micro-PET imaging with PC3-xenografted mice evaluated the radiotracers’ specific binding and pharmacokinetics. Results: 18F-Fluorinated compounds were obtained with radiochemical yields up to 5% (decay-corrected) and average molar activity of 53 GBq.µmol 1. Cell and lung section experiments indicated specific binding which was blocked up to 75% after pretreatment with arginase inhibitors. Micro-PET studies indicated fast clearance of the radiotracers (7.3±0.6 min), arginase-mediated uptake, and a selective tumor accumulation (standardized uptake value: 3.0±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 the uptake in control and arginase-inhibited PC3 xenografted mice. These results encourage further research to examine the suitability of 18F-FBMARS to select patients for treatments with arginase inhibitors.