title: [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-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.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Woosuk
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Thuc M
authors.initials: TM
authors.lastname: Le
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Liu
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Soumya
authors.initials: S
authors.lastname: Poddar
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Jimmy
authors.initials: J
authors.lastname: Bazzy
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Xuemeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Nhu T
authors.initials: NT
authors.lastname: Uong
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Evan R
authors.initials: ER
authors.lastname: Abt
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Capri
authors.affiliation: Abcam, Cambridge, MA 02139-1517;
authors.forename: Wayne R
authors.initials: WR
authors.lastname: Austin
authors.affiliation: Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095;
authors.forename: Juno S
authors.initials: JS
authors.lastname: Van Valkenburgh
authors.affiliation: Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095;
authors.forename: Dalton
authors.initials: D
authors.lastname: Steele
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095;
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Gipson
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Roger
authors.initials: R
authors.lastname: Slavik
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Cabebe
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Thotsophon
authors.initials: T
authors.lastname: Taechariyakul
authors.affiliation: CellSight Technologies, Inc., San Francisco, CA 94107;
authors.forename: Shahriar S
authors.initials: SS
authors.lastname: Yaghoubi
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095;
authors.forename: Jason T
authors.initials: JT
authors.lastname: Lee
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Saman
authors.initials: S
authors.lastname: Sadeghi
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607;
authors.forename: Arnon
authors.initials: A
authors.lastname: Lavie
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; The Pasarow Mass Spectrometry Laboratory, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095; Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA 90095;
authors.forename: Kym F
authors.initials: KF
authors.lastname: Faull
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Department of Microbiology, Immunology, & Molecular Genetics, University of California, Los Angeles, CA 90095; Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095; Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095;
authors.forename: Owen N
authors.initials: ON
authors.lastname: Witte
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Crump Institute for Molecular Imaging, University of California, Los Angeles, CA 90095; cradu@mednet.ucla.edu mphelps@mednet.ucla.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Phelps
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Ken
authors.initials: K
authors.lastname: Herrmann
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
authors.forename: Johannes
authors.initials: J
authors.lastname: Czernin
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; cradu@mednet.ucla.edu mphelps@mednet.ucla.edu.
authors.forename: Caius G
authors.initials: CG
authors.lastname: Radu
mesh_terms: D000227:Adenine Nucleotides / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001087:Arabinonucleosides / Q000737:chemistry*; D014408:Biomarkers, Tumor / Q000737:chemistry*; D045744:Cell Line, Tumor; D000077866:Clofarabine; D003287:Contrast Media / Q000737:chemistry; D003842:Deoxycytidine Kinase / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000201:enzymology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D049268:Positron-Emission Tomography / Q000379:methods*; D011355:Prodrugs / Q000737:chemistry; D051381:Rats
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D014408:Biomarkers, Tumor; D003287:Contrast Media; D011355:Prodrugs; D000077866:Clofarabine; D003842:Deoxycytidine Kinase
keywords: PET imaging; cancer; deoxycytidine kinase; nucleotide metabolism