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Journal of Nuclear Medicine Vol. 51 No. 1 121-129
© 2010 by Society of Nuclear Medicine
doi: 10.2967/jnumed.109.066126

Basic Science Investigation

124I-Iodopyridopyrimidinone for PET of Abl Kinase–Expressing Tumors In Vivo

Mikhail Doubrovin*,1, Tatiana Kochetkova*,1, Elmer Santos*,1, Darren R. Veach1, Peter Smith-Jones1, Nagavarakishore Pillarsetty1, Julius Balatoni1,2, William Bornmann2, Juri Gelovani2 and Steven M. Larson1

1 Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; and 2 Department of Experimental Diagnostic Imaging, M.D. Anderson Cancer Center, Houston, Texas

Correspondence: For correspondence or reprints contact: Steven Larson, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., S212C, New York, NY 10021. E-mail: larsons{at}mskcc.org

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. We also 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.

Key Words: tyrosine kinase inhibitor • BCR-Abl • in vivo imaging • direct tracer • PET

COPYRIGHT © 2010 by the Society of Nuclear Medicine, Inc.

* Contributed equally to this work.


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