TY - JOUR
T1 - Improved Radiosynthesis and Biological Evaluations of L- and D-1-[18F]Fluoroethyl-Tryptophan for PET Imaging of IDO-Mediated Kynurenine Pathway of Tryptophan Metabolism
AU - Xin, Yangchun
AU - Cai, Hancheng
N1 - Funding Information:
We would like to thank Prof. Xiankai Sun for providing insight that greatly assisted our work, Robert Hallgren for producing F for radiochemistry study, and Hussein Diab for acquiring and analyzing the micro-PET/CT imaging study. We also thank Drs. William Silvers, Guiyang Hao, and Aditi Mulgaonkar for their assistance in this study. This work was supported by Cancer Prevention Research Institute of Texas (CPRIT) Grant (RP110771), the Simmons Cancer Center Grant (NIH 5P30 CA 142543), and American Cancer Society and the Simmons Cancer Center (ACS-IRG-02-196). 18
Publisher Copyright:
© 2016, World Molecular Imaging Society.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - Cancer
KW - IDO
KW - Kynurenine pathway
KW - PET imaging
KW - Radiosynthesis
KW - Tryptophan metabolism
UR - http://www.scopus.com/inward/record.url?scp=84994386116&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994386116&partnerID=8YFLogxK
U2 - 10.1007/s11307-016-1024-z
DO - 10.1007/s11307-016-1024-z
M3 - Article
C2 - 27815661
AN - SCOPUS:84994386116
SN - 1536-1632
VL - 19
SP - 589
EP - 598
JO - Molecular Imaging and Biology
JF - Molecular Imaging and Biology
IS - 4
ER -