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[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

ABSTRACT: Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-?-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-?-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [(18)F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [(18)F]F-AraG is a better substrate for dGK than for dCK. [(18)F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [(18)F]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [(18)F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [(18)F]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [(18)F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [(18)F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.

SUBMITTER: Kim W

PROVIDER: S-EPMC4839461 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

Kim Woosuk W Le Thuc M TM Wei Liu L Poddar Soumya S Bazzy Jimmy J Wang Xuemeng X Uong Nhu T NT Abt Evan R ER Capri Joseph R JR Austin Wayne R WR Van Valkenburgh Juno S JS Steele Dalton D Gipson Raymond M RM Slavik Roger R Cabebe Anthony E AE Taechariyakul Thotsophon T Yaghoubi Shahriar S SS Lee Jason T JT Sadeghi Saman S Lavie Arnon A Faull Kym F KF Witte Owen N ON Donahue Timothy R TR Phelps Michael E ME Herschman Harvey R HR Herrmann Ken K Czernin Johannes J Radu Caius G CG

Proceedings of the National Academy of Sciences of the United States of America 20160328 15

Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro ...[more]

PMID: 27035974

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[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

Publications

[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity.

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