Novel PET Probes Specific for Deoxycytidine Kinase

Journal of Nuclear Medicine

Andrew Q. Tran¹  Michael E. Phelps¹  Dean O. Campbell¹  Johannes Czernin¹  Jordan C. Wengrod¹  Nagichettiar Satyamurthy¹  Jason T. Lee¹  Owen N. Witte¹  Caius G. Radu¹  Chengyi J. Shu¹ 

关键词: deoxycytidine kinase (dCK);    cytidine deaminase (CDA);    PET probes;    deoxyribonucleoside salvage;    autoimmune;    malignant lymphoproliferation;   

DOI  :  10.2967/jnumed.109.073361

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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.

【 授权许可】

Unknown