Preclinical Evaluation of 11 C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer.

Sarcosine is a known substrate of proton-coupled amino acid transporters (PATs), which are overexpressed in selected tissues and solid tumors. Sarcosine, an N -methyl derivative of the amino acid glycine and a metabolic product of choline, plays an important role for prostate cancer aggressiveness and progression. Methods: 11 C-radiolabeled sarcosine was tested as a new PET imaging probe in comparison with 11 C-choline in 2 prostate cancer tumor xenograft models (DU-145 and PC-3). We characterized 11 C-sarcosine transport in PC-3 and LNCaP tumor cells and performed 11 C-sarcosine PET with CT in the first human subject with localized Gleason 4 + 3 prostate cancer. Target metabolite analyses of sarcosine and its natural precursors, glycine and choline, were performed from independent human prostate tissues. Results: In vitro assays indicated blockage of 11 C-sarcosine uptake into PC-3 and LNCaP tumor cells by excess unlabeled (cold) sarcosine. 5-hydroxy-l-tryptophan, but not 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, competitively inhibited 11 C-sarcosine tumor cell uptake, confirming PAT-mediated transport. In vivo tumor-to-background ratios (TBRs) obtained from 11 C-sarcosine PET were significantly elevated compared with 11 C-choline in DU-145 (TBR: 1.92 ± 0.11 for 11 C-sarcosine vs. 1.41 ± 0.13 for 11 C-choline [ n = 10; P < 0.002]) and PC-3 tumors (TBR: 1.89 ± 0.2 for 11 C-sarcosine vs. 1.34 ± 0.16 for 11 C-choline [ n = 7; P < 0.002]). 11 C-sarcosine produced high-contrast images in 1 case of localized clinically significant prostate cancer. Target metabolite analyses revealed significant stepwise increases of sarcosine, glycine, and choline tissue levels from benign prostate tissue to localized prostate cancer and subsequently metastatic disease. 11 C-sarcosine showed a favorable radiation dosimetry with an effective dose estimate of 0.0045 mSv/MBq, resulting in 2.68 mSv for a human subject (600-MBq dose). Conclusion: 11 C-sarcosine is a novel radiotracer for PATs and shows initial utility for prostate cancer imaging, with potential benefit over commonly used 11 C-choline.