In Vivo Imaging of Bcr-Abl Overexpressing Tumors with a Radiolabeled Imatinib Analog as an Imaging Surrogate for Imatinib

Gleevec (imatinib mesylate; Novartis International AG) is a tyrosine kinase inhibitor that was approved by the U.S. Food and Drug Administration in 2001 for the treatment of chronic adult myelogenous leukemia, in 2002 for the treatment of gastrointestinal stromal tumor, and in 2003 for the treatment of pediatric chronic myeloid leukemia. Imatinib is currently under investigation in numerous clinical trials for other malignancies such as advanced breast (NCT00372476, NCT00323063), hormone-refractory prostate (NCT00427999), and ovarian carcinomata (NCT00840450, NCT00928642) as either a monotherapy agent or in combination therapies with other drugs, including docetaxel, capecitabine, and sorafenib. Imatinib has been shown to inhibit multiple tyrosine kinases, including Bcr-Abl, c-Kit, and platelet-derived growth factor receptor (PDGFRα) (1). The Bcr-Abl protein is a dysregulated tyrosine kinase that is present in 95% of all chronic myeloid leukemia patients; its formation is caused by a fusion oncogene called BCR-ABL (2). In the original clinical trial of imatinib in patients with chronic myeloid leukemia, 95% of patients showed a complete hematologic response and 94% of patients showed a complete cytogenetic remission of the disease (3). In contrast, most gastrointestinal stromal tumor cells have a mutation in the coding genes for KIT and in the PDGFRα domain; these mutations prompt the activation of c-Kit, which in turn results in increased tumor growth (4). The crystal structure of imatinib in the binding pocket of Abl has been characterized and has shown that imatinib binds preferentially to the inactive conformation of the enzyme with the activation loop in the closed conformation (5). In addition, the crystal structure also revealed that any modifications made to the methyl group of piperazine should not affect binding since this part of the molecule lies outside the binding pocket (Fig. 1). Figure 1 Depiction of imatinib in crystal structure of imatinib/Abl complex (5) (A) and molecular modeling of SKI696 (B) into kinase binding domain of Abl based on crystal structure. Gray = hydrogen; red = oxygen; dark blue = nitrogen; light green = fluorine; ... Other groups have reported radiolabeled analogs of imatinib, with most attempting the use of 14C (6,7) or tritium (8). An 11C-imatinib analog has been synthesized and used for PET of baboons to examine the biodistribution and pharmacokinetics of imatinib (9). The plan to modify imatinib with radioactive fluorine was also pursued by Peng et al., who reported an 18F-radiolabeled derivative of imatinib that was used to measure c-Kit expression (10). A metabolite of imatinib was reported in which the piperazinyl methyl group was replaced by a hydrogen atom; this analog was shown to maintain its activity (11). Because the loss of the methyl group does not alter the activity, that position of the molecule can be considered a potential point of chemical modification. On the basis of these observations, the decision was made in this current study to modify the chemical structure of imatinib at the piperazinyl methyl group by substituting the methyl group with a fluoroethyl group. Confident that a modest modification at this position would not affect the binding or activity of the drug, we began synthesis of the 2-fluoroethyl derivative of imatinib (SKI-247696, SKI696). The overall goal of this study was to design a targeting agent that could be used to determine whether tumors were likely to take up imatinib before therapy, thus leading to personalized treatment for patients.