Abstract
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Objectives: Assessment of tumor metabolism by non-invasive means can facilitate accurate diagnosis and staging as well as selection of an appropriate therapeutic strategy and monitoring response to treatment. [18F]FDG has not proven to be a reliable probe for assessing metabolism in prostate cancer. Metabolic substrates labeled with carbon-11 represent promising alternatives as they can be completely catabolized and/or incorporated into larger biomolecules. Pyruvate is the nexus of cellular metabolism, where it is predominantly oxidized in cells with a lipogenic phenotype and reduced in cells with a glycolytic phenotype. We hypothesize that these different pathways can be differentiated by measuring the flux of radioactivity through tissue following administration of [11C]pyruvate. Alanine is a source of pyruvate and may also be an independent probe that captures utilization of amino acids for biomass production. Our aim was to prepare L-[3-11C]alanine and [3-11C]pyruvate and evaluate their ability to characterize the metabolic phenotype of two different prostate cancer cell lines by positron emission tomography (PET).
Methods: L-[3-11C]Alanine was synthesized by alkylation of a Schiff base precursor with [11C]CH3I in the presence of chiral cinchonidium phase transfer catalyst. [3-11C]Pyruvate was synthesized from D/L-[3-11C]alanine using D-amino acid oxidase, alanine racemase, and catalase. The flux of radioactivity through LNCaP and PC3 xenograft tumors was determined following intravenous administration of the 11C-labeled metabolite in Tris buffer to male nu/nu tumor-bearing mice. A 30-minute dynamic PET acquisition (6 x 5 min slices) was performed beginning approximately 10 min post injection. Time-activity curves (TACs) were derived for each tracer in both LNCaP and PC3 xenografted tumors.
Results: L-[3-11C]Alanine was prepared in 15.9 ± 11.3% decay-corrected radiochemical yield (dcRCY), >99% radiochemical purity (RCP) and >95% enantiomeric excess in 38 ± 2 min from end-of-bombardment (EOB). [3-11C]Pyruvate was prepared in 18.5 ± 2.2% dcRCY and >99% RCP in 52 ± 4 min from EOB. Activity in LNCaP tumors following [3-11C]pyruvate administration increases with time and is significantly higher than in PC3 tumors. The trends are reversed for L-[3-11C]alanine, which increases with time in PC3 tumors and exceeds activity in LNCaP tumors.
Conclusions: L-[3-11C]Alanine and [3-11C]pyruvate are produced rapidly and in high RCP. These tracers can be used in tandem to assess the metabolic phenotype of prostate cancer by PET. High uptake and retention of [3-11C]pyruvate in LNCaP tumors is consistent with a lipogenic phenotype. By contrast, high utilization of L-[3-11C]alanine and lower retention of [3-11C]pyruvate in PC3 tumors is consistent with a more aggressive glycolytic phenotype.
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