(124)I-Iodopyridopyrimidinone for PET of Abl kinase-expressing tumors in vivo Journal Article
| Authors: | Doubrovin, M.; Kochetkova, T.; Santos, E.; Veach, D. R.; Smith-Jones, P.; Pillarsetty, N.; Balatoni, J.; Bornmann, W.; Gelovani, J.; Larson, S. M. |
| Article Title: | (124)I-Iodopyridopyrimidinone for PET of Abl kinase-expressing tumors in vivo |
| Abstract: | 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. Copyright © 2010 by the Society of Nuclear Medicine, Inc. |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; nonhuman; positron emission tomography; radiopharmaceuticals; binding affinity; neoplasms; imatinib; drug inhibition; animal experiment; animal model; protein binding; rna, small interfering; in vivo study; cancer cell culture; cytotoxicity; tumor xenograft; cell line, tumor; abelson kinase; chronic myeloid leukemia; drug specificity; pyridones; pyrimidines; blotting, western; isotope labeling; enzyme inhibitors; rat; positron-emission tomography; radiopharmaceutical agent; protein-tyrosine kinases; tyrosine kinase inhibitor; pet; bcr-abl; direct tracer; in vivo imaging; iodopyridopyrimidinone i 124; binding, competitive; k562 cells |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 51 |
| Issue: | 1 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2010-01-01 |
| Start Page: | 121 |
| End Page: | 129 |
| Language: | English |
| DOI: | 10.2967/jnumed.109.066126 |
| PUBMED: | 20048131 |
| PROVIDER: | scopus |
| PMCID: | PMC4432838 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 2" - "Export Date: 20 April 2011" - "CODEN: JNMEA" - "Source: Scopus" |
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61Balatoni -
134Pillarsetty -
98Veach -
25
Santos -
67
Smith-Jones -
959Larson -
97
Doubrovin
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