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

Kim, Woosuk; Le, Thuc M.; Wei, Liu; Poddar, Soumya; Bazzy, Jimmy; Wang, Xuemeng; Uong, Nhu T.; Abt, Evan R.; Capri, Joseph R.; Austin, Wayne R.; Van Valkenburgh, Juno S.; Steele, Dalton; Gipson, Raymond M.; Slavik, Roger; Cabebe, Anthony E.; Taechariyakul, Thotsophon; Yaghoubi, Shahriar S.; Lee, Jason T.; Sadeghi, Saman; Lavie, Arnon; Faull, Kym F.; Witte, Owen N.; Donahue, Timothy R.; Phelps, Michael E.; Herschman, Harvey R.; Herrmann, Ken; Czernin, Johannes; Radu, Caius G.

doi:10.1073/pnas.1524212113

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

Journal Article · Mon Mar 28 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1524212113· OSTI ID:1244296

Kim, Woosuk; Le, Thuc M.; Wei, Liu; Poddar, Soumya; Bazzy, Jimmy; Wang, Xuemeng; Uong, Nhu T.; Abt, Evan R.; Capri, Joseph R.; Austin, Wayne R.; Van Valkenburgh, Juno S.; Steele, Dalton; Gipson, Raymond M.; Slavik, Roger; Cabebe, Anthony E.; Taechariyakul, Thotsophon; Yaghoubi, Shahriar S.; Lee, Jason T.; Sadeghi, Saman; Lavie, Arnon more »

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. In order to identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds—[¹⁸F]Clofarabine; 2-chloro-2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosyl-adenine ([¹⁸F]CFA) and 2'-deoxy-2'-[¹⁸F]fluoro-9-β-D-arabinofuranosyl-guanine ([¹⁸F]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, [¹⁸F]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [¹⁸F]F-AraG is a better substrate for dGK than for dCK. [¹⁸F]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [¹⁸F]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 [¹⁸F]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [¹⁸F]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 [¹⁸F]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [¹⁸F]CFA PET as a new cancer biomarker for treatment stratification and monitoring.

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Research Organization:: Univ. of California, Los Angeles, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Contributing Organization:: AstraZeneca, Cambridge (United Kingdom)

Grant/Contract Number:: SC0012353; R25 CA098010; P50 CA086306; R01 CA187678

OSTI ID:: 1244296

Alternate ID(s):: OSTI ID: 1469293

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Vol. 113 Journal Issue: 15; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 56 works

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

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