RT Journal Article SR Electronic T1 Novel PET Probes Specific for Deoxycytidine Kinase JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1092 OP 1098 DO 10.2967/jnumed.109.073361 VO 51 IS 7 A1 Chengyi J. Shu A1 Dean O. Campbell A1 Jason T. Lee A1 Andrew Q. Tran A1 Jordan C. Wengrod A1 Owen N. Witte A1 Michael E. Phelps A1 Nagichettiar Satyamurthy A1 Johannes Czernin A1 Caius G. Radu YR 2010 UL http://jnm.snmjournals.org/content/51/7/1092.abstract AB Deoxycytidine kinase (dCK) is a rate-limiting enzyme in the deoxyribonucleoside salvage pathway and a critical determinant of therapeutic activity for several nucleoside analog prodrugs. We have previously reported the development of 1-(2′-deoxy-2′-18F-fluoro-β-d-arabinofuranosyl)cytosine (18F-FAC), a new probe for PET of dCK activity in immune disorders and certain cancers. The objective of the current study was to develop PET probes with improved metabolic stability and specificity for dCK. Toward this goal, several candidate PET probes were synthesized and evaluated in vitro and in vivo. Methods: High-pressure liquid chromatography was used to analyze the metabolic stability of 18F-FAC and several newly synthesized analogs with the natural d-enantiomeric sugar configuration or the corresponding unnatural l-configuration. In vitro kinase and uptake assays were used to determine the affinity of the 18F-FAC l-nucleoside analogs for dCK. The biodistribution of selected l-analogs in mice was determined by small-animal PET/CT. Results: Candidate PET probes were selected using the following criteria: low susceptibility to deamination, high affinity for purified recombinant dCK, high uptake in dCK-expressing cell lines, and biodistribution in mice reflective of the tissue-expression pattern of dCK. Among the 10 newly developed candidate probes, 1-(2′-deoxy-2′-18F-fluoro-β-l-arabinofuranosyl)cytosine (l-18F-FAC) and 1-(2′-deoxy-2′-18F-fluoro-β-l-arabinofuranosyl)-5-methylcytosine (l-18F-FMAC) most closely matched the selection criteria. The selection of l-18F-FAC and l-18F-FMAC was validated by showing that these two PET probes could be used to image animal models of leukemia and autoimmunity. Conclusion: Promising in vitro and in vivo data warrant biodistribution and dosimetry studies of l-18F-FAC and l-18F-FMAC in humans.