Your browser doesn't support javascript.
loading
[18F]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.
Afiliação
  • Kim W; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Le TM; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Wei L; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Poddar S; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Bazzy J; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Wang X; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Uong NT; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Abt ER; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Capri JR; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Austin WR; Abcam, Cambridge, MA 02139-1517;
  • Van Valkenburgh JS; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095;
  • Steele D; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095;
  • Gipson RM; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095;
  • Slavik R; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Cabebe AE; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Taechariyakul T; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Yaghoubi SS; CellSight Technologies, Inc., San Francisco, CA 94107;
  • Lee JT; 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;
  • Sadeghi S; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Lavie A; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607;
  • Faull KF; 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 Ca
  • Witte ON; 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
  • Donahue TR; 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;
  • Phelps ME; 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.
  • Herschman HR; 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
  • Herrmann K; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Czernin J; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095; Ahmanson Translational Imaging Division, University of California, Los Angeles, CA 90095;
  • Radu CG; 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.
Proc Natl Acad Sci U S A ; 113(15): 4027-32, 2016 Apr 12.
Article em En | MEDLINE | ID: mdl-27035974
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-ß-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-ß-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.
Assuntos
Palavras-chave
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Arabinonucleosídeos / Nucleotídeos de Adenina / Biomarcadores Tumorais / Desoxicitidina Quinase / Tomografia por Emissão de Pósitrons Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2016 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Arabinonucleosídeos / Nucleotídeos de Adenina / Biomarcadores Tumorais / Desoxicitidina Quinase / Tomografia por Emissão de Pósitrons Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2016 Tipo de documento: Article