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

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

Proceedings of the National Academy of Sciences of the United States of America (2016-04-02)
Woosuk Kim, Thuc M Le, Liu Wei, Soumya Poddar, Jimmy Bazzy, Xuemeng Wang, Nhu T Uong, Evan R Abt, Joseph R Capri, Wayne R Austin, Juno S Van Valkenburgh, Dalton Steele, Raymond M Gipson, Roger Slavik, Anthony E Cabebe, Thotsophon Taechariyakul, Shahriar S Yaghoubi, Jason T Lee, Saman Sadeghi, Arnon Lavie, Kym F Faull, Owen N Witte, Timothy R Donahue, Michael E Phelps, Harvey R Herschman, Ken Herrmann, Johannes Czernin, Caius G Radu
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-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-DGUOK antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-CDA (C-term) antibody produced in rabbit, saturated ammonium sulfate (SAS) precipitated, buffered aqueous solution