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

被引：66

作者：

Kim, Woosuk ^{[1
,2
]}

Le, Thuc M. ^{[1
,2
]}

Wei, Liu ^{[1
,2
]}

Poddar, Soumya ^{[1
,2
]}

Bazzy, Jimmy ^{[1
,2
]}

Wang, Xuemeng ^{[1
,2
]}

Uong, Nhu T. ^{[1
,2
]}

Abt, Evan R. ^{[1
,2
]}

Capri, Joseph R. ^{[1
,2
]}

Austin, Wayne R. ^{[3
]}

Van Valkenburgh, Juno S. ^{[2
,4
]}

Steele, Dalton ^{[2
,4
]}

Gipson, Raymond M. ^{[4
]}

Slavik, Roger ^{[1
,2
]}

Cabebe, Anthony E. ^{[1
,2
]}

Taechariyakul, Thotsophon ^{[1
,2
]}

Yaghoubi, Shahriar S. ^{[5
]}

Lee, Jason T. ^{[1
,6
]}

Sadeghi, Saman ^{[1
,2
]}

Lavie, Arnon ^{[7
]}

Faull, Kym F. ^{[1
,2
,8
,9
]}

Witte, Owen N. ^{[1
,10
,11
,12
]}

Donahue, Timothy R. ^{[1
,2
,13
]}

Phelps, Michael E. ^{[1
,6
]}

Herschman, Harvey R. ^{[1
,2
,14
]}

Herrmann, Ken ^{[1
,2
]}

Czernin, Johannes ^{[1
,2
]}

Radu, Caius G. ^{[1
,2
]}

机构：

[1] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Ahmanson Translat Imaging Div, Los Angeles, CA 90095 USA

[3] Abcam, Cambridge, MA 02139 USA

[4] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA

[5] CellSight Technol Inc, San Francisco, CA 94107 USA

[6] Univ Calif Los Angeles, Crump Inst Mol Imaging, Los Angeles, CA 90095 USA

[7] Univ Illinois, Dept Biochem & Mol Genet, Chicago, IL 60607 USA

[8] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Pasarow Mass Spectrometry Lab, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[11] Univ Calif Los Angeles, Howard Hughes Med Inst, Los Angeles, CA 90095 USA

[12] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA 90095 USA

[13] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA

[14] Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2016年 / 113卷 / 15期

关键词：

nucleotide metabolism; deoxycytidine kinase; PET imaging; cancer; POSITRON-EMISSION-TOMOGRAPHY; DEOXYGUANOSINE KINASE; THYMIDINE KINASE; IN-VIVO; NUCLEOSIDE; TUMOR; MITOCHONDRIAL; DEAMINASE; EXPRESSION; ADENOSINE;

D O I：

10.1073/pnas.1524212113

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-[F-18]Clofarabine; 2-chloro-2'-deoxy-2'-[F-18]fluoro-9-beta-D-arabinofuranosyl-adenine ([F-18]CFA) and 2'-deoxy-2'-[F-18]fluoro-9-beta-D-arabinofuranosylguanine ([F-18]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, [F-18]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [F-18]F-AraG is a better substrate for dGK than for dCK. [F-18]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [F-18]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 [F-18]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [F-18]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 [F-18]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [F-18]CFA PET as a new cancer biomarker for treatment stratification and monitoring.

引用

页码：4027 / 4032

页数：6

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