[<sup>18</sup>F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity

Woo-Suk Kim(University of California, Los Angeles), Thuc Le(University of California, Los Angeles), Wei Liu(University of California, Los Angeles), Soumya Poddar(University of California, Los Angeles), Jimmy Bazzy(University of California, Los Angeles), Xuemeng Wang(University of California, Los Angeles), Nhu T. Uong(University of California, Los Angeles), Evan R. Abt(University of California, Los Angeles), Joseph Capri(University of California, Los Angeles), Wayne R. Austin(Abcam (United States)), Juno S. Van Valkenburgh(University of California, Los Angeles), Dalton Steele(University of California, Los Angeles), Raymond M. Gipson(University of California, Los Angeles), Roger Slavik(University of California, Los Angeles), Anthony E. Cabebe(University of California, Los Angeles), Thotsophon Taechariyakul(University of California, Los Angeles), Shahriar Yaghoubi(CellSight Technologies (United States)), Jason T. Lee(University of California, Los Angeles), Saman Sadeghi(University of California, Los Angeles), Arnon Lavie(University of Illinois Chicago), Kym F. Faull(Salk Institute for Biological Studies), Owen N. Witte(Howard Hughes Medical Institute), Timothy R. Donahue(University of California, Los Angeles), Michael E. Phelps(University of California, Los Angeles), Harvey R. Herschman(University of California, Los Angeles), Ken Herrmann(University of California, Los Angeles), Johannes Czernin(University of California, Los Angeles), Caius G. Radu(University of California, Los Angeles)
Proceedings of the National Academy of Sciences
March 28, 2016
10.1073/pnas.1524212113
Cited by 87Open Access
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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.

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