Development of 1-N-11C-Methyl-l- and -d-Tryptophan for pharmacokinetic imaging of the immune checkpoint inhibitor 1-Methyl-Tryptophan

• Published in: Scientific reports 2015-11, Vol.5 (1), p.16417, Article 16417
• Main Authors: Xie, Lin, Maeda, Jun, Kumata, Katsushi, Yui, Joji, Zhang, Yiding, Hatori, Akiko, Nengaki, Nobuki, Wakizaka, Hidekatsu, Fujinaga, Masayuki, Yamasaki, Tomoteru, Shimoda, Yoko, Higuchi, Makoto, Suhara, Tetsuya, Wang, Feng, Zhang, Ming-Rong
• Format: Article
• Language: English
• Subjects: 59; 59/78; 631/154/436/2388; 631/1647/245/2092; Carbon dioxide; Computed tomography; Dioxygenase; Humanities and Social Sciences; Immune checkpoint; Immunotherapy; Isomers; Kidneys; multidisciplinary; Pancreas; Pharmacokinetics; Probes; Radioactivity; Science; Stereoisomers; Tryptophan
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep16417

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 ). A long-standing debate exists in immunology and oncology: which stereoisomer has the potential of antitumor immunotherapy. Herein, we developed two novel radioprobes, 1- N - 11 C-methyl- l - and - d -tryptophan ( 11 C- l -1MTrp and 11 C- d -1MTrp), without modifying the chemical structures of the two isomers and investigated their utility for pharmacokinetic imaging of the whole body. 11 C- l -1MTrp and 11 C- d -1MTrp were synthesized rapidly with radiochemical yields of 47 ± 6.3% (decay-corrected, based on 11 C-CO 2 ), a radiochemical purity of >98%, specific activity of 47–130 GBq/μmol and high enantiomeric purity. PET/CT imaging in rats revealed that for 11 C- l -1MTrp, the highest distribution of radioactivity was observed in the pancreas, while for 11 C- D -1MTrp, it was observed in the kidney. Ex vivo biodistribution confirmed the PET/CT results, indicating the differences in pharmacokinetics between the two isomers. Both 11 C- l -1MTrp and 11 C- 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.