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

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.