Presentation Development of 1-N-[11C]-Methyl-L- and -D-Tryptophan for Pharmacokinetic Imaging of the Immune Checkpoint Inhibitor 1-Methyl-Tryptophan

Xie, Lin  ,  Maeda, Jun  ,  Kumata, Katsushi  ,  Yui, Joji  ,  Zhang, Yiding  ,  Hatori, Akiko  ,  Nengaki, Nobuki  ,  Wakizaka, Hidekatsu  ,  Fujinaga, Masayuki  ,  Ming-Rong, Zhang

Objectives: 1-Methyl-tryptophan (1MTrp) is known as a specific inhibitor targeting the immune- checkpoint protein indoleamine-2,3-dioxygenase, in two stereoisomers of levorotary (L) and dextrorotary (D) (1). A long-standing debate exists in immunology and oncology: which stereoisomer has the potential of antitumor immunotherapy (2). As a first step to disentangle the potential and explore the possibility of pharmacokinetic imaging in immunotherapy, we here developed two novel radioprobes, 1-N-[11C]methyl-L- and -D-tryptophan ([11C]L-1MTrp and [11C]D-1-MTrp), without modifying the chemical structures of the two isomers, and delineated their pharmacokinetic imaging in whole body. 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. The pharmacokinetics of the L and D isomers were tracked using dynamic PET/CT scans and biodistribution study after the radioprobes injection.Results: [11C]L-1MTrp and [11C]D-1MTrp were obtained with radiochemical yields of 47 ± 6.3% (decay-corrected, based on [11C]CO2), a radiochemical purity of > 98%, specific activity of 47130 GBq/μmol, and high enantiomeric purity. PET/CT imaging in rats revealed that for [11C]L-1MTrp, the highest distribution of radioactivity was observed in the pancreas, while for [11C]D-1MTrp, it was observed in the kidney (Fig. 1). Ex vivo biodistribution confirmed the PET/CT results, indicating the differences in pharmacokinetics between the two isomers. Conclusion: Both [11C]L-1MTrp and [11C]D-1MTrp are therefore useful PET probes for delineating the distribution and action of the checkpoint inhibitor 1MTrp in vivo. This study represents the first step toward using whole-body and real-time insight to disentangle the antitumor potential of the two stereoisomers of 1MTrp, and it can facilitate the development of 1MTrp immunotherapy.
Ninth Japan-China Joint Seminar on Radiopharmaceutical Chemistry

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