Improved Radiosynthesis and Biological Evaluations of L- and D-1-[18F]Fluoroethyl-Tryptophan for PET Imaging of IDO-Mediated Kynurenine Pathway of Tryptophan Metabolism

Xin, Yangchun; Cai, Hao

doi:10.1007/s11307-016-1024-z

Cited by 36 publications

(44 citation statements)

References 27 publications

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“…Furthermore, the tryptophan analog, 1-D-methyl-tryptophan (1-D-MT) has proven to be superior to its L-counterpart and has been widely used in the clinic. Nevertheless, similar to previous findings in a breast cancer model 33,46 , our studies in Smo/Smo mice showed that the brain uptake of 1-D-[ 18 F]FETrp was very low as compared to that of its L-counterpart, possibly due to preference differences in the amino acid transporter. However, it should be noted that although the tumor uptake of 1-D-[ 18 F]FETrp in Smo/Smo mice was low, it was still slightly higher than that in the normal brain regions (contralateral cerebellum and cerebrum).…”

Section: Discussionsupporting

confidence: 91%

“…It is common that the L-enantiomer of an amino acid PET tracer has higher tumor uptake than its D-counterpart 39,40 . Consistent with this, in breast cancer, it has previously been shown that L-and D-enantiomers of 1-[ 18 F]FETrp have different uptake profiles 33 . In these studies, the in vitro cell uptake in MDA-MB-231 cells and the in vivo tumor uptake in MDA-MB-231 mouse xenografts suggested that the uptake of 1-L-[ 18 F]FETrp is much higher than the D-counterpart.…”

Section: Specificity Of the 1-l-[ 18 F]fetrp Uptake In Medulloblastomsupporting

confidence: 71%

“…, a tryptophan analog, has been successfully used to evaluate the increased tryptophan metabolism through KP in patients with brain tumors [18][19][20][21][22][23][24][25] . However, the short half-life of the carbon-11 isotope has limited the broad applications in clinical research and significant effort has been made in developing 18 F-labeled tryptophan tracers 15,17,[32][33][34][35][36] . Recent in vitro and in vivo studies suggest that a novel PET tracer, 1-(2-…”

mentioning

confidence: 99%

“…, might have similar transport and metabolic properties as [ 11 C]AMT ( Fig. 1), and could be used to assess abnormal tryptophan metabolism via the KP in brain tumors [32][33][34] .…”

mentioning

confidence: 99%

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PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin

Yue

et al. 2020

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In vivo positron emission tomography (pet) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[ 18 F]fluoroethyl)-L-tryptophan (1-L-[ 18 f]fetrp) as a pet imaging probe for this common malignant pediatric brain tumor. 1-L-[ 18 F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/ Smo medulloblastoma mice with constitutive actvation of the Smoothened (Smo) receptor using a PerkinElmer G4 PET-X-Ray scanner. Medulloblastoma showed significant and specific accumulation of 1-L-[ 18 F]FETrp. 1-L-[ 18 F]FETrp also showed significantly higher tumor uptake than its D-enantiomer, 1-D-[ 18 F]FETrp. The uptake of 1-L-[ 18 F]FETrp in the normal brain tissue was low, suggesting that 1-L-[ 18 f] fetrp may prove a valuable pet imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors.

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Section: Discussionsupporting

confidence: 91%

Section: Specificity Of the 1-l-[ 18 F]fetrp Uptake In Medulloblastomsupporting

confidence: 71%

mentioning

confidence: 99%

“…, might have similar transport and metabolic properties as [ 11 C]AMT ( Fig. 1), and could be used to assess abnormal tryptophan metabolism via the KP in brain tumors [32][33][34] .…”

mentioning

confidence: 99%

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PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

Xin

Yue

et al. 2020

Sci Rep

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“…Recent developments for noninvasive in vivo metabolite imaging may provide a solution for this technical hurdle. 105,106 It should be noted, however, that systemic Trp levels can be affected by TDO, which is expressed in the liver constitutively and induced in some types of cancer, 42 suggesting that evaluation of this amino acid is not necessarily a sole reflection of IDO1 enzyme activity. Finally, understanding how IDO1 works in cancer cells, versus noncancer cells, in terms of the enzyme and signal transduction properties, is essential for targeting the full effects of this pleiotropic mediator of immune suppression.…”

Section: Ido1 Inhibitors In Cancer Immunotherapymentioning

confidence: 99%

IDO1 in cancer: a Gemini of immune checkpoints

et al. 2018

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Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival. Given the high expression of IDO1 among multiple cancer types along with the lack of monotherapeutic efficacy, these data suggest that there is a more complex mechanism of action than previously appreciated. Similar to the dual faces of the astrological Gemini, we highlight the multiple roles of IDO1 and review its canonical association with IDO1-dependent tryptophan metabolism, as well as documented evidence confirming the dispensability of enzyme activity for its immunosuppressive effects. The gene transcript levels for IDO1 highlight its strong association with T-cell infiltration, but the lack of a universal prognostic significance among all cancer subtypes. Finally, ongoing clinical trials are discussed with consideration of IDO1-targeting strategies that enhance the efficacy of immunotherapy for cancer patients.

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Automated radiosynthesis of 1‐(2‐[¹⁸F]fluoroethyl)‐L‐tryptophan ([¹⁸F]FETrp) for positron emission tomography (PET) imaging of cancer in humans

Jiang

Guo

Cai

et al. 2023

Labelled Comp Radiopharmac

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The radiotracer 1-(2-[ 18 F]fluoroethyl)-L-tryptophan (L-[ 18 F]FETrp or [ 18 F] FETrp) is a substrate of indoleamine 2,3-dioxygenase, the initial and key enzyme of the kynurenine pathway associated with tumoral immune resistance. In preclinical positron emission tomography studies, [ 18 F]FETrp is highly accumulated in a wide range of primary and metastatic cancers, such as lung cancer, prostate cancer, and gliomas. However, the clinical translation of this radiotracer into the first-in-human trial has not been reported, partially due to its racemization during radiofluorination which renders the purification of the final product challenging. However, efficient purification is essential for human studies in order to assure radiochemical and enantiomeric purity. In this work, we report a fully automated radiosynthesis of [ 18 F]FETrp on a Synthra RNPlus research module, including a one-pot two steps radiosynthesis, dual independent chiral and reverse-phase semipreparative high-performance liquid chromatography purifications, and solid-phase extraction-assisted formulation. The presented approach has led to its Investigational New Drug application and approval that allows the testing of this tracer in humans.

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Improved Radiosynthesis and Biological Evaluations of L- and D-1-[18F]Fluoroethyl-Tryptophan for PET Imaging of IDO-Mediated Kynurenine Pathway of Tryptophan Metabolism

Abstract: We have developed a practical method for the automatic radiosynthesis of 1-L-[F]FETrp and 1-D-[F]FETrp. Our biological evaluation results suggest that 1-L-[F]FETrp is a promising radiotracer for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism in cancer.

Cited by 36 publications

References 27 publications

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

IDO1 in cancer: a Gemini of immune checkpoints

Automated radiosynthesis of 1‐(2‐[¹⁸F]fluoroethyl)‐L‐tryptophan ([¹⁸F]FETrp) for positron emission tomography (PET) imaging of cancer in humans

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Improved Radiosynthesis and Biological Evaluations of L- and D-1-[18F]Fluoroethyl-Tryptophan for PET Imaging of IDO-Mediated Kynurenine Pathway of Tryptophan Metabolism

Abstract: We have developed a practical method for the automatic radiosynthesis of 1-L-[F]FETrp and 1-D-[F]FETrp. Our biological evaluation results suggest that 1-L-[F]FETrp is a promising radiotracer for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism in cancer.

Cited by 36 publications

References 27 publications

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

PET imaging of medulloblastoma with an 18F-labeled tryptophan analogue in a transgenic mouse model

IDO1 in cancer: a Gemini of immune checkpoints

Automated radiosynthesis of 1‐(2‐[18F]fluoroethyl)‐L‐tryptophan ([18F]FETrp) for positron emission tomography (PET) imaging of cancer in humans

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Automated radiosynthesis of 1‐(2‐[¹⁸F]fluoroethyl)‐L‐tryptophan ([¹⁸F]FETrp) for positron emission tomography (PET) imaging of cancer in humans