N (1)-Fluoroalkyltryptophan Analogues: Synthesis and in vitro Study as Potential Substrates for Indoleamine 2,3-Dioxygenase

Jean Henrottin; Astrid Zervosen; Christian Lemaire; Frédéric Sapunaric; Sophie Laurent; Benoit Van den Eynde; Serge Goldman; Alain Plenevaux; André Luxen

doi:10.1021/ml500385d

N (1)-Fluoroalkyltryptophan Analogues: Synthesis and in vitro Study as Potential Substrates for Indoleamine 2,3-Dioxygenase

ACS Med Chem Lett. 2015 Jan 25;6(3):260-5. doi: 10.1021/ml500385d. eCollection 2015 Mar 12.

Authors

Jean Henrottin¹, Astrid Zervosen², Christian Lemaire², Frédéric Sapunaric², Sophie Laurent², Benoit Van den Eynde³, Serge Goldman⁴, Alain Plenevaux², André Luxen²

Affiliations

¹ Cyclotron Research Center, Department of Chemistry, and Macromolécules Biologiques, Center for Protein Engineering, Université de Liège, Sart-Tilman , B-4000 Liège, Belgium ; Cyclotron Research Center, Department of Chemistry, and Macromolécules Biologiques, Center for Protein Engineering, Université de Liège, Sart-Tilman , B-4000 Liège, Belgium.
² Cyclotron Research Center, Department of Chemistry, and Macromolécules Biologiques, Center for Protein Engineering, Université de Liège, Sart-Tilman , B-4000 Liège, Belgium.
³ Ludwig Institute for Cancer Research, Brussels Branch and de Duve Institute, Université Catholique de Louvain , B-1200 Brussels, Belgium.
⁴ PET/Biomedical Cyclotron Unit and Department of Nuclear Medicine, Erasme Hospital, Université Libre de Bruxelles , B-1070 Brussels, Belgium ; Center for Microscopy and Molecular Imaging , Rue Adrienne Bolland 8, B-6041 Gosselies, Belgium.

Abstract

Indoleamine 2,3-dioxygenase (hIDO) is an enzyme that catalyzes the oxidative cleavage of the indole ring of l-tryptophan through the kynurenine pathway, thereby exerting immunosuppressive properties in inflammatory and tumoral tissues. The syntheses of 1-(2-fluoroethyl)-tryptophan (1-FETrp) and 1-((1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl)methyl)-tryptophan, two N (1)-fluoroalkylated tryptophan derivatives, are described here. In vitro enzymatic assays with these two new potential substrates of hIDO show that 1-FETrp is a good and specific substrate of hIDO. Therefore, its radioactive isotopomer, 1-[(18)F]FETrp, should be a molecule of choice to visualize tumoral and inflammatory tissues and/or to validate new potential inhibitors.

Keywords: 1-(2-fluoroethyl)-tryptophan; Tryptophan; indoleamine 2,3-dioxygenase; kynurenine; positron emission tomography; tryptophan 2,3-dioxygenase.