Preclinical Evaluation of 11C-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:¹¹C-radiolabeled sarcosine was tested as a new PET imaging probe in comparison with ¹¹C-choline in 2 prostate cancer tumor xenograft models (DU-145 and PC-3). We characterized ¹¹C-sarcosine transport in PC-3 and LNCaP tumor cells and performed ¹¹C-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 ¹¹C-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 ¹¹C-sarcosine tumor cell uptake, confirming PAT-mediated transport. In vivo tumor-to-background ratios (TBRs) obtained from ¹¹C-sarcosine PET were significantly elevated compared with ¹¹C-choline in DU-145 (TBR: 1.92 ± 0.11 for ¹¹C-sarcosine vs. 1.41 ± 0.13 for ¹¹C-choline [n = 10; P < 0.002]) and PC-3 tumors (TBR: 1.89 ± 0.2 for ¹¹C-sarcosine vs. 1.34 ± 0.16 for ¹¹C-choline [n = 7; P < 0.002]). ¹¹C-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. ¹¹C-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:¹¹C-sarcosine is a novel radiotracer for PATs and shows initial utility for prostate cancer imaging, with potential benefit over commonly used ¹¹C-choline.