N¹-Fluoroalkyltryptophan Analogues: Synthesis and in vitro Study as Potential Substrates for Indoleamine 2,3-Dioxygenase

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.

Assessment of Tryptophan Uptake and Kinetics Using 1-(2-18F-Fluoroethyl)-l-Tryptophan and α-11C-Methyl-l-Tryptophan PET Imaging in Mice Implanted with Patient-Derived Brain Tumor Xenografts

“…Importantly, 18 F-FETrp could also be useful to estimate tryptophan metabolism via IDO1, IDO2, or TDO2. This is supported by in vitro data demonstrating markedly higher 18 F-FETrp accumulation in IDO1-expressing P815B-mIDO1 cl6 cells than in P815B-IDO1-negative cl1 cells (33,34). Notably, high 18 F-FETrp accumulation in P815B-mIDO1 cl6 cells was blocked by 1-methyl-L-tryptophan, an IDO1 inhibitor, suggesting this radiotracer is a promising candidate for imaging in vivo IDO1 enzyme activity.…”

“…Most studies focused on radiosynthesis, biodistribution, or tracer transport, which could be blocked by L-type amino acid transporter 1 inhibition. Recently, 1-(2-fluoroethyl)-L-tryptophan (FETrp) was tested as a potential substrate for human IDO1 and TDO2 in in vitro enzymatic assays (33,34). FETrp showed variable consumption depending on the human IDO1 concentration and incubation time and appeared to be a better substrate of human IDO1 than a-D,L-methyl-tryptophan.…”

[18F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor‐Bearing Mice

“…Scheme shows the preparation of picolinaldehydes 12 a , b , and their coupling to 6 a , b to provide the two pairs of analogues 2 , 13 and 14 a , b . Treatment of 6‐methylpyridin‐3‐ol with 2‐fluoroethyl‐4‐methylbenzene sulfonate in the presence of potassium carbonate and sodium iodide led to 10 a . The methyl group of 10 a was oxidized following a published synthetic sequence to yield aldehyde 12 a , which was condensed with 6 a , b in the presence of acetic acid and 2‐picoline‐borane to give target compounds 2 and 13 .…”

“…Scheme2 shows the preparation of picolinaldehydes 12 a,b, and their coupling to 6a,b to provide the two pairs of analogues 2, 13 and 14 a,b.T reatment of 6-methylpyridin-3-ol with 2-fluoroethyl-4-methylbenzene sulfonate [16] in the presence of potassium carbonate and sodium iodide led to 10 a. The methyl group of 10 a was oxidizedf ollowing ap ublished synthetic sequence [17] to yield aldehyde 12 a,w hich was condensed with 6a,b in the presence of acetic acid and 2-picoline-borane to give target compounds 2 and 13.A lternatively, alkylation of 6-methylpyridin-3-ol with 2-(2-chloroethoxy)ethan-1-ola nd subsequenttreatment with tetrabutylammonium fluorideg ave 10 b.O xidation of the methyl group led to 12 b, which was condensed with 6a or 6b to provide target compounds 14 a,b.F inally,P d/C-catalyzed hydrogenation of 13 yielded the saturated analogue 15.…”

Synthesis, Stability and Reactivity of α‐Fluorinated Azidoalkanes

“…[40,52,56,57] An azide useful for the 18 F positron emission tomography application is 1-azido-2-fluoroethane, which is used for imaginga fter click reactions with various alkynes. [58][59][60][61][62] Scheme33. Staudinger reaction of fluorinated azides with P III compounds.…”