Imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level.

Abstract We synthesized two series of imatinib mesylate (STI-571) analogs to develop a Bcr-Abl and c - KIT receptor-specific labeling agent for positron emission tomography (PET) imaging to measure Bcr-Abl and c - KIT expression levels in a mouse model. The methods of molecular modeling, synthesis of STI-571 and its analogs, in vitro kinase assays, and radiolabeling are described. Molecular modeling revealed that these analogs bind the same Bcr-Abl and c - KIT binding sites as those bound by STI-571. The analogs potently inhibit the tyrosine kinase activity of Bcr-Abl and c - KIT , similarly to STI-571. [ 18 F]-labeled STI-571 was prepared with high specific activity (75 GBq/μmol) by nucleophilic displacement and an average radiochemical yield of 12%. [ 131 I]-labeled STI-571 was prepared with high purity (>95%) and an average radiochemical yield of 23%. The uptake rates of [ 18 F]-STI-571 in K562 cells expressing Abl and in U87WT cells overexpressing c - KIT were significantly higher than those in the U87 cell and could be inhibited by STI-71 (confirming the specificity of uptake). PET scans of K562 and U87WT tumor-bearing mice with [ 18 F]-STI-571 as a contrast agent showed visible tumor uptake and tumor-to-non-target contrast.