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Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography.

ABSTRACT: PURPOSE:(11)C-Choline-positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts. EXPERIMENTAL DESIGN:(11)C-Choline, (11)C-methyl-[1,2-(2)H(4)]-choline ((11)C-D4-choline), and (18)F-D4-choline were synthesized to permit comparison. Biodistribution, metabolism, small-animal PET studies, and kinetic analysis of tracer uptake were carried out in human colon HCT116 xenograft-bearing mice. RESULTS:Oxidation of choline analogs to betaine was highest with (11)C-choline, with reduced oxidation observed with (11)C-D4-choline and substantially reduced with (18)F-D4-choline, suggesting that both fluorination and deuteration were important for tracer metabolism. Although all tracers were converted intracellularly to labeled phosphocholine (specific signal), the higher rate constants for intracellular retention (K(i) and k(3)) of (11)C-choline and (11)C-D4-choline, compared with (18)F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of (18)F-D4-choline in three tumors with similar radiotracer delivery (K(1)) and choline kinase ? expression-HCT116, A375, and PC3-M-were the same, suggesting that (18)F-D4-choline has utility for cancer detection irrespective of histologic type. CONCLUSION:We have shown here that both deuteration and fluorination combine to provide protection against choline oxidation in vivo. (18)F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation.

SUBMITTER: Witney TH

PROVIDER: S-EPMC6485417 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography.

Witney Timothy H TH Alam Israt S IS Turton David R DR Smith Graham G Carroll Laurence L Brickute Diana D Twyman Frazer J FJ Nguyen Quang-Dé QD Tomasi Giampaolo G Awais Ramla O RO Aboagye Eric O EO

Clinical cancer research : an official journal of the American Association for Cancer Research 20120110 4

<h4>Purpose</h4>(11)C-Choline-positron emission tomography (PET) has been exploited to detect the aberrant choline metabolism in tumors. Radiolabeled choline uptake within the imaging time is primarily a function of transport, phosphorylation, and oxidation. Rapid choline oxidation, however, complicates interpretation of PET data. In this study, we investigated the biologic basis of the oxidation of deuterated choline analogs and assessed their specificity in human tumor xenografts.<h4>Experimen ...[more]

PMID: 22235095

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography.

Publications

Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography.

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