title: Preclinical Evaluation of11C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer.
abstract: Sarcosine is a known substrate of proton-coupled amino acid transporters (PATs), which are overexpressed in selected tissues and solid tumors. Sarcosine, anN-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 with11C-choline in 2 prostate cancer tumor xenograft models (DU-145 and PC-3). We characterized11C-sarcosine transport in PC-3 and LNCaP tumor cells and performed11C-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 of11C-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 inhibited11C-sarcosine tumor cell uptake, confirming PAT-mediated transport. In vivo tumor-to-background ratios (TBRs) obtained from11C-sarcosine PET were significantly elevated compared with11C-choline in DU-145 (TBR: 1.92 ± 0.11 for11C-sarcosine vs. 1.41 ± 0.13 for11C-choline [n= 10;P< 0.002]) and PC-3 tumors (TBR: 1.89 ± 0.2 for11C-sarcosine vs. 1.34 ± 0.16 for11C-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 used11C-choline.
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan mpiert@umich.edu.
authors.forename: Morand
authors.initials: M
authors.lastname: Piert
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Xia
authors.initials: X
authors.lastname: Shao
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: David
authors.initials: D
authors.lastname: Raffel
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Mathew S
authors.initials: MS
authors.lastname: Davenport
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Montgomery
authors.affiliation: Pathology Department, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Lakshmi Priya
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Hockley
authors.affiliation: Pathology Department, University of Michigan, Ann Arbor, Michigan; and.|Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Department of Radiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Peter J H
authors.initials: PJH
authors.lastname: Scott
authors.affiliation: Pathology Department, University of Michigan, Ann Arbor, Michigan; and.|Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Pathology Department, University of Michigan, Ann Arbor, Michigan; and.|Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Thekkelnaycke
authors.initials: T
authors.lastname: Rajendiran
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism*; D002250:Carbon Radioisotopes; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011522:Protons; D011874:Radiometry; D012521:Sarcosine / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D026905:Amino Acid Transport Systems; D002250:Carbon Radioisotopes; D011522:Protons; D012521:Sarcosine
keywords: 11C-sarcosine; prostate cancer; proton-coupled amino acid transporter (PAT)