¹²⁴I-Iodopyridopyrimidinone for PET of Abl kinase-expressing tumors in vivo

Because of the recent development of an iodopyridopyrimidinone Abl protein kinase inhibitor (PKI), ¹²⁴I-SKI-212230 (¹²⁴I-SKI230), we investigated the feasibility of a PET-based molecular imaging method for the direct visualization of Abl kinase expression and PKI treatment. Methods: In vitro pharmacokinetic properties, including specific and nonspecific binding of ¹²⁴I-SKI230 to its Abl kinase target and interaction with other PKIs, were assessed in cell-free medium and chronic myelogenous leukemia (CML) cells overexpressing BCR-Abl (K562), in comparison with BT-474 cells that are low in Abl expression. In a xenograft tumor model, we assessed the in vivo pharmacokinetics of ¹²⁴I-SKI230 using PET and postmortem tissue sampling.Wealso tested a paradigm of ¹²⁴I-SKI230 PET after treatment of the animal with a dose of Abl-specific PKI for the monitoring of the tumor response. Results: In vitro studies confirmed that SKI230 binds to Abl kinase with nanomolar affinity, that selective uptake occurs in cell lines known to express Abl kinase, that RNAi knock-down supports specificity of cellular uptake due to Abl kinase, and that imatinib, an archetype Abl PKI, completely displaces SKI230. With SKI230, we obtained successful in vivo PET of Abl-expressing human tumors in a nude rat. We were also able to demonstrate evidence of substrate inhibition of in vivo radiotracer uptake in the xenograft tumor after treatment of the animal as a model of PKI treatment monitoring. Conclusion: These results support the hypothesis that molecular imaging using PET will be useful for the study of in vivo pharmacodynamics of Abl PKI molecular therapy in humans.