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

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]CFAmore » 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.« less
Authors:
 [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [3] ;  [4] ;  [1] ;  [1] ;  [1] ;  [5] ;  [6] ;  [1] ;  [7] more »;  [8] ;  [9] ;  [10] ;  [6] ;  [11] ;  [1] ;  [1] ;  [1] « less
  1. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
  2. Abcam, Cambridge, MA (United States)
  3. Univ. of California, Los Angeles, CA (United States). Ahmanson Translational Imaging Division and Dept. of Chemistry and Biochemistry
  4. Univ. of California, Los Angeles, CA (United States). Dept. of Chemistry and Biochemistry
  5. CellSight Technologies, Inc., San Francisco, CA (United States)
  6. Univ. of California, Los Angeles, CA (United States). Dept. of Molecular and Medical Pharmacology and Crump Inst. for Molecular Imaging
  7. Univ. of Illinois, Chicago, IL (United States). Dept. of Biochemistry and Molecular Genetics
  8. Univ. of California, Los Angeles, CA (United States). The Pasarow Mass Spectrometry Lab., Semel Inst. for Neuroscience and Human Behavior, Dept. of Psychiatry and Biobehavioral Sciences, Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
  9. Univ. of California, Los Angeles, CA (United States). Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, Howard Hughes Medical Inst., Dept. of Microbiology, Immunology, and Molecular Genetics and Dept. of Molecular and Medical Pharmacology
  10. Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine, Dept. of Surgery, Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
  11. Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine, Dept. of Biological Chemistry, Dept. of Molecular and Medical Pharmacology and Ahmanson Translational Imaging Division
Publication Date:
Grant/Contract Number:
SC0012353; R25 CA098010; P50 CA086306; R01 CA187678
Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 15; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Univ. of California, Los Angeles, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Contributing Orgs:
AstraZeneca, Cambridge (United Kingdom)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; 59 BASIC BIOLOGICAL SCIENCES; nucleotide metabolism; deoxycytidine kinase; PET imaging; cancer
OSTI Identifier:
1244296
Alternate Identifier(s):
OSTI ID: 1469293

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, and Radu, Caius G.. [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. United States: N. p., Web. doi:10.1073/pnas.1524212113.
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.. [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. United States. doi:10.1073/pnas.1524212113.
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, and Radu, Caius G.. 2016. "[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity". United States. doi:10.1073/pnas.1524212113.
@article{osti_1244296,
title = {[18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity},
author = {Kim, Woosuk and Le, Thuc M. and Wei, Liu and Poddar, Soumya and Bazzy, Jimmy and Wang, Xuemeng and Uong, Nhu T. and Abt, Evan R. and Capri, Joseph R. and Austin, Wayne R. and Van Valkenburgh, Juno S. and Steele, Dalton and Gipson, Raymond M. and Slavik, Roger and Cabebe, Anthony E. and Taechariyakul, Thotsophon and Yaghoubi, Shahriar S. and Lee, Jason T. and Sadeghi, Saman and Lavie, Arnon and Faull, Kym F. and Witte, Owen N. and Donahue, Timothy R. and Phelps, Michael E. and Herschman, Harvey R. and Herrmann, Ken and Czernin, Johannes and Radu, Caius G.},
abstractNote = {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.},
doi = {10.1073/pnas.1524212113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 15,
volume = 113,
place = {United States},
year = {2016},
month = {3}
}