TY - JOUR
T1 - Evaluation of deuterated 18F- and 11C-labeled choline analogs for cancer detection by positron emission tomography
AU - Witney, Timothy H.
AU - Alam, Israt S.
AU - Turton, David R.
AU - Smith, Graham
AU - Carroll, Laurence
AU - Brickute, Diana
AU - Twyman, Frazer J.
AU - Nguyen, Quang Dé
AU - Tomasi, Giampaolo
AU - Awais, Ramla O.
AU - Aboagye, Eric O.
PY - 2012/2/15
Y1 - 2012/2/15
N2 - Purpose: 11C-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: 11C-Choline, 11C-methyl-[1,2- 2H 4]-choline ( 11C-D4-choline), and 18F-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 11C-choline, with reduced oxidation observed with 11C-D4-choline and substantially reduced with 18F-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 11C-choline and 11C-D4-choline, compared with 18F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of 18F-D4-choline in three tumors with similar radiotracer delivery (K 1) and choline kinase a expression - HCT116, A375, and PC3-M - were the same, suggesting that 18F-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. 18F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation.
AB - Purpose: 11C-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: 11C-Choline, 11C-methyl-[1,2- 2H 4]-choline ( 11C-D4-choline), and 18F-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 11C-choline, with reduced oxidation observed with 11C-D4-choline and substantially reduced with 18F-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 11C-choline and 11C-D4-choline, compared with 18F-D4-choline, were explained by the rapid conversion of the nonfluorinated tracers to betaine within HCT116 tumors. Imaging studies showed that the uptake of 18F-D4-choline in three tumors with similar radiotracer delivery (K 1) and choline kinase a expression - HCT116, A375, and PC3-M - were the same, suggesting that 18F-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. 18F-D4-choline showed the highest selectivity for phosphorylation and warrants clinical evaluation.
UR - http://www.scopus.com/inward/record.url?scp=84857069334&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84857069334&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-11-2462
DO - 10.1158/1078-0432.CCR-11-2462
M3 - Article
C2 - 22235095
AN - SCOPUS:84857069334
VL - 18
SP - 1063
EP - 1072
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 4
ER -