Presentation Radiosynthesis and pharmacokinetic comparison of 1-N-[11C]methyl]-L- and -D-tryptophan

Kumata, Katsushi  ,  Xie, Lin  ,  Yui, Joji  ,  Hatori, Akiko  ,  Zhang, Yiding  ,  Nengaki, Nobuki  ,  Fujinaga, Masayuki  ,  Yamasaki, Tomoteru  ,  Shimoda, Yoko  ,  Maeda, Jun  ,  Ming-Rong, Zhang

2015-05-28
Description
Objectives: The indole-containing small molecule 1-methyl-tryptophan (1MTrp) is known as a specific inhibitor targeted immune checkpoint protein indoleamine-2,3-dioxygenase (IDO)- switching off the effector T cells of the immune system to support tumor growth. 1MTrp has shown attractive antitumor activity without noticeable toxicity [1], and its phase I trial had been completed in 2014. However, 1MTrp exists as 2 stereoisomers of L and D. Most preclinical studies have employed the racemic mixture, thus leaving a long-standing debate in immunology and oncology, which stereoisomers have the potential of immune checkpoint inhibitor [2,3]. To remove the blindfold of 1MTrp effects and guide its immunotherapy development, we synthesized 1-N-[11C]methyl]-L- and -D-tryptophan ([11C]L-1MTrp and [11C]D-1-MTrp) and compared their pharmacokinetics by PET.Methods: [11C]L-1MTrp and [11C]D-1MTrp were synthesized by reaction of the corresponding Boc-Trp-OEt with [11C]CH3I at 80 °C for 5 min, followed by deprotection with 2 N HCl at 100 °C for 5 min. Pharmacokinetics of the L and D isomers were compared by dynamic PET scans and biodistribution study following the injection of the radioprobes in rats. Results: [11C]L-1MTrp and [11C]D-1MTrp were obtained with radiochemical yields of 47.0 ± 6.3% (n = 80, based on [11C]CO2, EOS), radiochemical purity of > 98%, and specific activity of 47―130 GBq/μmol, showing high enantiomeric purity. PET imaging in rats revealed [11C]L-1MTrp had the highest accumulation of radioactivity (SUV 2.88 ± 0.03) in the pancreas with high IDO expression, while [11C]D-1MTrp showed the highest uptake (SUV 1.16 ± 0.03) in the kidney at 60 min after the radioprobes injection respectively. Ex vivo biodistribution results supported the PET images and indicated that uptake of L isomer in each organ was significantly higher than D isomer except in the kidney. Quite different tissue distribution was verified between the 2 stereoisomers. Conclusions: Both [11C]L-1MTrp and [11C]D-1MTrp are useful PET probes for tracking the pharmacokinetics of 1MT in vivo. Imaging the immune checkpoint inhibitors would enable us to take a new look at cancer immunotherapy and drug development.Reference: [1].Muller AJ, et al. Nat Med. 2005;11:312. [2]. Hou DY, et al. Cancer Res. 2007;67:792. [3] Lob S, et al. Blood. 2008;111:2152.
21st International Symposium on Radiopharmaceutical Sciences

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