Preparation and evaluation of L- and D-5-[(18)F]fluorotryptophan as PET imaging probes for indoleamine and tryptophan 2,3-dioxygenases

Nuclear Medicine and Biology
Tang TangJan Marik

Abstract

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-[(18)F]fluorotryptophan with respect to its ability for measuring IDO1 and TDO2 activity by positron emission tomography (PET). L-5-[(18)F]fluorotryptophan and D-5-[(18)F]fluorotryptophan were synthesized by Cu(I) catalyzed [(18)F]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 407-740GBq/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 up...Continue Reading

Citations

Jan 30, 2018·Cellular & Molecular Immunology·Lijie ZhaiDerek A Wainwright
Sep 13, 2019·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Flóra JohnCsaba Juhász
Mar 1, 2020·Nature Protocols·Florian GuibbalVéronique Gouverneur
Nov 7, 2019·EJNMMI Radiopharmacy and Chemistry·Peter WierstraSandra Heskamp
Dec 11, 2019·British Journal of Cancer·Christiane A OpitzSaskia Trump

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