title: 18F-glutathione conjugate as a PET tracer for imaging tumors that overexpress L-PGDS enzyme.
abstract: Lipocalin-type prostaglandin D synthase (L-PGDS) has been correlated with the progression of neurological disorders. The present study aimed at evaluating the imaging potency of a glutathione conjugate of fluorine-18-labeled fluorobutyl ethacrynic amide ([18F]FBuEA-GS) for brain tumors. Preparation of [18F]FBuEA-GS has been modified from the -4-tosylate derivative via radiofluorination in 5% radiochemical yield. The mixture of nonradioactive FBuEA-GS derived from a parallel preparation has be resolved to two isomers in a ratio of 9:1 using analytic chiral reversed phase high performance liquid chromatography (RP-HPLC). The two fluorine-18-labeled isomers purified through nonchiral semipreparative RP-HPLC as a mixture were studied by assessing the binding affinity toward L-PGDS through a gel filtration HPLC, by analyzing radiotracer accumulation in C6 glioma cells, and by evaluating the imaging of radiotracer in a C6 glioma rat with positron emission tomography. The inhibition percentage of the production of PGD2 from PGH2 at the presence of 200 µM of FBuEA-GS and 4-Dibenzo[a,d]cyclohepten-5-ylidene-1-[4-(2H-tetrazol-5-yl)butyl]piperidine (AT-56) were 74.1 ± 4.8% and 97.6 ± 16.0%, respectively. [18F]FBuEA-GS bound L-PGDS (16.3-21.7%) but not the isoform, microsomal prostaglandin E synthase 1. No binding to GST-alpha and GST-pi was observed. The binding strength between [18F]FBuEA-GS and L-PGDS has been evaluated using analytic gel filtration HPLC at the presence of various concentrations of the cold competitor FBuEA-GS. The contrasted images indicated that the radiotracer accumulation in tumor lesions is probably related to the overexpression of L-PGDS.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan.
authors.forename: Ho-Lien
authors.initials: HL
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Chang-Gung memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ying-Cheng
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan.
authors.forename: Wei-Yuan
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Department of Surgery, Chang-Gung memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.affiliation: Department of Nuclear Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsinghua University, Hsinchu, Taiwan; Institute of Nuclear Engineering and Sciences, National Tsinghua University, Hsinchu, Taiwan.
authors.forename: Chung-Shan
authors.initials: CS
authors.lastname: Yu
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005462:Fluorine Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000737:chemistry* / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D054834:Lipocalins / Q000378:metabolism*; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D015230:Prostaglandin D2 / Q000096:biosynthesis; D044262:Prostaglandin H2 / Q000378:metabolism; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000577:Amides; D005462:Fluorine Radioisotopes; D054834:Lipocalins; D011849:Radioactive Tracers; D044262:Prostaglandin H2; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D005978:Glutathione; D015230:Prostaglandin D2
references.citation: Org Lett. 2011 Mar 18;13(6):1444-6
references.pmid: 21332154
references.citation: Biomaterials. 2013 Apr;34(13):3355-65
references.pmid: 23384791
references.citation: J Clin Oncol. 2007 Oct 20;25(30):4714-21
references.pmid: 17947718
references.citation: Neuro Oncol. 2013 Jan;15(1):41-56
references.pmid: 23115160
references.citation: Chem Rev. 2008 May;108(5):1501-16
references.pmid: 18426240
references.citation: Biochim Biophys Acta. 2013 May;1830(5):3217-66
references.pmid: 23036594
references.citation: Chem Rev. 2011 Oct 12;111(10):6231-98
references.pmid: 21526749
references.citation: J Neurochem. 2012 Jan;120(2):279-91
references.pmid: 22043816
references.citation: Bioconjug Chem. 2011 Mar 16;22(3):422-8
references.pmid: 21338096
references.citation: J Med Chem. 2010 Aug 12;53(15):5536-48
references.pmid: 20684598
references.citation: Target Oncol. 2009 Sep;4(3):151-68
references.pmid: 19768637
references.citation: J Labelled Comp Radiopharm. 2013 Mar-Apr;56(3-4):120-9
references.pmid: 24285318
references.citation: Neurochem Res. 2014 Jan;39(1):1-36
references.pmid: 24258018
references.citation: Chem Rev. 2010 May 12;110(5):3087-111
references.pmid: 20225899
references.citation: Mol Imaging Biol. 2013 Apr;15(2):131-5
references.pmid: 22869463
references.citation: Chem Rev. 2011 Oct 12;111(10):5821-65
references.pmid: 21942677
references.citation: J Pharmacol Exp Ther. 2011 Nov;339(2):716-25
references.pmid: 21865441
references.citation: Semin Nucl Med. 2011 Jul;41(4):265-82
references.pmid: 21624561
references.citation: Drug Metab Rev. 1997 Feb-May;29(1-2):413-580
references.pmid: 9187528
references.citation: Nat Rev Drug Discov. 2013 Dec;12(12):931-47
references.pmid: 24287781
references.citation: J Biol Chem. 2012 Mar 16;287(12):9414-28
references.pmid: 22275363
references.citation: J Biol Chem. 2009 Mar 20;284(12):7623-30
references.pmid: 19131342
references.citation: Bioorg Med Chem. 2012 Oct 1;20(19):5941-7
references.pmid: 22917858
references.citation: Nucl Med Biol. 2013 Apr;40(3):430-6
references.pmid: 23306136
references.citation: Semin Nucl Med. 2013 Nov;43(6):449-61
references.pmid: 24094712
references.citation: Nucl Med Biol. 2012 Nov;39(8):1202-12
references.pmid: 22784382
references.citation: J Registry Manag. 2013 Spring;40(1):32-5
references.pmid: 23778695
references.citation: J Med Chem. 2010 Feb 11;53(3):1015-22
references.pmid: 20055416
references.citation: Semin Nucl Med. 2012 Nov;42(6):356-70
references.pmid: 23026359
references.citation: Org Biomol Chem. 2010 Oct 21;8(20):4730-5
references.pmid: 20740244
references.citation: Bioorg Med Chem Lett. 2012 Jun 15;22(12):3998-4003
references.pmid: 22607679
references.citation: Chem Rev. 2011 Oct 12;111(10):5866-98
references.pmid: 21936577
references.citation: Science. 2011 Nov 4;334(6056):639-42
references.pmid: 22053044
references.citation: Nature. 2007 Aug 2;448(7153):613-6
references.pmid: 17632546
references.citation: Nucl Med Biol. 2011 May;38(4):477-83
references.pmid: 21531284
references.citation: J Nucl Med. 2005 Dec;46(12):1948-58
references.pmid: 16330557
references.citation: Nucl Med Biol. 2003 Nov;30(8):819-26
references.pmid: 14698785
references.citation: Eur J Nucl Med Mol Imaging. 2012 May;39(5):800-10
references.pmid: 22231017
references.citation: Amino Acids. 2009 Feb;36(2):283-95
references.pmid: 18414978
references.citation: Eur J Nucl Med Mol Imaging. 2012 Feb;39 Suppl 1:S11-30
references.pmid: 22388624
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Dec 27;829(1-2):1-25
references.pmid: 16253574
references.citation: Angew Chem Int Ed Engl. 2009;48(3):586-9
references.pmid: 19053117
references.citation: Adv Drug Deliv Rev. 2012 Jun 1;64(8):749-55
references.pmid: 21565234
references.citation: Cancer Res. 2012 Feb 15;72(4):845-53
references.pmid: 22202125
references.citation: Cancer Res. 2009 Oct 15;69(20):8025-34
references.pmid: 19808963
references.citation: Cancer Res. 2007 Oct 1;67(19):9248-57
references.pmid: 17909032
references.citation: Drug Metab Rev. 2011 May;43(2):300-6
references.pmid: 21495795
references.citation: Biochem J. 2012 Apr 1;443(1):75-84
references.pmid: 22248185