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Molecular Imaging and Biology

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01-08-2017 | Research Article

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

Authors: Yangchun Xin, Hancheng Cai

Published in: Molecular Imaging and Biology | Issue 4/2017

Abstract

Purpose

Tryptophan metabolism via indoleamine 2,3-dioxygenase (IDO)-mediated kynurenine pathway plays a role in immunomodulation and has been emerging as a plausible target for cancer immunotherapy. Imaging IDO-mediated kynurenine pathway of tryptophan metabolism with positron emission tomography (PET) could provide valuable information for noninvasive assessment of cancer immunotherapy response. In this work, radiotracer 1-(2-[¹⁸F]fluoroethyl)-L-tryptophan (1-L-[¹⁸F]FETrp) and its enantioisomer 1-D-[¹⁸F]FETrp were synthesized and evaluated for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism.

Procedures

Enantiopure 1-L-[¹⁸F]FETrp and 1-D-[¹⁸F]FETrp were prepared by a nucleophilic reaction of N-boc-1-(2-tosylethyl) tryptophan tert-butyl ester with [¹⁸F]Fluoride, followed by acid hydrolysis in a GE Tracerlab FX-N module. In vitro cell uptake assays were performed with a breast cancer cell line MDA-MB-231. Small animal PET/computed tomography (CT) imaging was carried out in a mouse model bearing MDA-MB-231 xenografts.

Results

Automatic radiosynthesis of 1-L-[¹⁸F]FETrp and 1-D-[¹⁸F]FETrp was achieved by a one-pot two-step approach in 19.0 ± 7.0 and 9.0 ± 3.0 % (n = 3) decay-corrected yield with radiochemical purity over 99 %, respectively. In vitro cell uptake study indicated the uptake of 1-D-[¹⁸F]FETrp in MDA-MB-231 cells was 0.73 ± 0.07 %/mg of protein at 60 min, while, the corresponding uptake of 1-L-[¹⁸F]FETrp was 6.60 ± 0.77 %/mg. Further mechanistic assays revealed that amino acid transport systems L-tpye amino acid transporter (LAT) and alanine-, serine-, and cysteine-preferring (ASC), and enzyme IDO expression were involved in cell uptake of 1-L-[¹⁸F]FETrp. Small animal PET/CT imaging study showed the tumor uptake of 1-L-[¹⁸F]FETrp was 4.6 ± 0.4 % ID/g, while, the tumor uptake of 1-D-[¹⁸F]FETrp was low to 1.0 ± 0.2 % ID/g, which were confirmed by ex vivo biodistribution study.

Conclusions

We have developed a practical method for the automatic radiosynthesis of 1-L-[¹⁸F]FETrp and 1-D-[¹⁸F]FETrp. Our biological evaluation results suggest that 1-L-[¹⁸F]FETrp is a promising radiotracer for PET imaging of IDO-mediated kynurenine pathway of tryptophan metabolism in cancer.

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Title: Improved Radiosynthesis and Biological Evaluations of L- and D-1-[18F]Fluoroethyl-Tryptophan for PET Imaging of IDO-Mediated Kynurenine Pathway of Tryptophan Metabolism
Authors: Yangchun Xin
Hancheng Cai
Publication date: 01-08-2017
Publisher: Springer US
Published in: Molecular Imaging and Biology / Issue 4/2017
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-016-1024-z

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Purpose

Procedures

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Procedures

Results

Conclusions

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