67308-26-3Relevant articles and documents
Preparation and evaluation of L- and D-5-[18F]fluorotryptophan as PET imaging probes for indoleamine and tryptophan 2,3-dioxygenases
Tang, Tang,Gill, Herman S.,Ogasawara, Annie,Tinianow, Jeff N.,Vanderbilt, Alexander N.,Williams, Simon-Peter,Hatzivassiliou, Georgia,White, Sharla,Sandoval, Wendy,DeMent, Kevin,Wong, Mengling,Marik, Jan
, p. 10 - 17 (2017/05/16)
Indoleamine and tryptophan 2,3-dioxygenases (IDO1 and TDO2) are pyrrolases catalyzing the oxidative cleavage of the 2,3-double bond of L-tryptophan in kynurenine pathway. In the tumor microenvironment, their increased activity prevents normal immune function, i.e. tumor cell recognition and elimination by cytotoxic T-cells. Consequently, inhibition of the kynurenine pathway may enhance the activity of cancer immunotherapeutics by reversing immune dysfunction. We sought to investigate the properties of radiolabeled 5-[18F]fluorotryptophan with respect to its ability for measuring IDO1 and TDO2 activity by positron emission tomography (PET). Results L-5-[18F]fluorotryptophan and D-5-[18F]fluorotryptophan were synthesized by Cu(I) catalyzed [18F]fluorodeboronylation of Boc/tBu protected precursors in moderate yields (1.5?±?0.6%) sufficient for pre-clinical studies. The specific activity of the product was 407–740?GBq/μmol, radiochemical purity >99% and enantiomeric excess 90–99%. Enzymatic assay confirmed that L-5-fluorotryptophan is an IDO1 and TDO2 substrate whereas the D-isomer is not. In-vitro cell uptake experiments using CT26 cells with doxycycline-induced overexpression of human-IDO1 and human-TDO2 revealed an elevated cell uptake of L-5-[18F]fluorotryptophan upon induction of IDO1 or TDO2 enzymes compared to baseline; however, the uptake was observed only in the presence of low L-tryptophan levels in media. PET imaging experiments performed using tumor bearing mouse models expressing IDO1 at various levels (CT26, CT26-hIDO1, 17082A, 17095A) showed tumor uptake of the tracer elevated up to 8%ID/g; however, the observed tumor uptake could not be attributed to IDO1 activity in the tumor tissue. The metabolism of L- and D- isomers was markedly different in vivo, the D-isomer was excreted by a combination of hepatobiliary and renal routes, the L-isomer underwent extensive metabolism to [18F]fluoride. Conclusion The observed in vivo tumor uptake of the tracer could not be attributed to IDO1 or TDO2 enzyme activity in the tumor, presumably due to competition with endogenous tryptophan as well as rapid tracer metabolism.
Synthesis and biological evaluation of 18F-labeled fluoropropyl tryptophan analogs as potential PET probes for tumor imaging
Chiotellis, Aristeidis,Mu, Linjing,Müller, Adrienne,Selivanova, Svetlana V.,Keller, Claudia,Schibli, Roger,Kr?mer, Stefanie D.,Ametamey, Simon M.
, p. 768 - 780 (2013/12/04)
In the search for an efficient, fluorine-18 labeled amino acid based radiotracer for tumor imaging with positron emission tomography (PET), two new tryptophan analogs were synthesized and characterized in vitro and in vivo. Both are tryptophan alkyl-derivatives, namely 2-(3-[18F]fluoropropyl)-dl- tryptophan ([18F]2-FPTRP) and 5-(3-[18F]fluoro-propyl)-dl- tryptophan ([18F]5-FPTRP). Standard reference compounds and precursors were prepared by multi step approaches. Radiosynthesis was achieved by no-carrier-added nucleophilic [18F]fluorination in 29-34% decay corrected yields with radiochemical purity over 99%. In vitro cell uptake assays showed that both compounds are substrates for amino acid transport and enter small cell lung cancer cells (NCI-H69) most probably almost exclusively via large neutral amino acids transporter(s) (LAT). Small animal PET imaging with xenograft bearing mice revealed high tumor/background ratios for [ 18F]2-FPTRP comparable to the well established tyrosine analog O-(2-[18F]fluroethyl)-l-tyrosine ([18F]FET). Radiometabolite studies showed no evidence of involvement of a biotransformation step in tumor accumulation.
Hemoglobin S antigelation agents based on 5-bromotryptophan with potential for sickle cell anemia
De Croos,Sangdee,Stockwell,Kar,Thompson,Johnson,Currie
, p. 3138 - 3142 (2007/10/02)
5-Bromotryptophan (5-BrTrp) is the most potent amino acid derivative reported in the literature to inhibit the gelation of hemoglobin S (from sickle cell anemia patients). Trp-Trp is also more potent than Trp as an antigelation agent. Therefore, we have prepared a series of dipeptides containing 5-BrTrp and evaluated the antigelation activity. 5-BrTrp-5-BrTrp is the most potent, i.e., 5.9 times the activity of Trp, followed by 5-BrTrp-Trp and then Trp-5-BrTrp. This improved antigelation potency for 5-BrTrp-5-BrTrp and 5-BrTrp-Trp is very significant and will be pursued further as lead compounds with potential for sickle cell anemia.
