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), (124)I-SKI-212230 ((124)I-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 (124)I-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 (124)I-SKI230 using PET and postmortem tissue sampling. We also tested a paradigm of (124)I-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Doubrovin
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kochetkova
authors.forename: Elmer
authors.initials: E
authors.lastname: Santos
authors.forename: Darren R
authors.initials: DR
authors.lastname: Veach
authors.forename: Peter
authors.initials: P
authors.lastname: Smith-Jones
authors.forename: Nagavarakishore
authors.initials: N
authors.lastname: Pillarsetty
authors.forename: Julius
authors.initials: J
authors.lastname: Balatoni
authors.forename: William
authors.initials: W
authors.lastname: Bornmann
authors.forename: Juri
authors.initials: J
authors.lastname: Gelovani
authors.forename: Steven M
authors.initials: SM
authors.lastname: Larson
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D007553:Isotope Labeling; D020014:K562 Cells; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011728:Pyridones / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics; D034741:RNA, Small Interfering; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics
chemical_list: C546822:2-(4-iodophenylamino)pyrido(2,3-d)pyrimidin-7-one; D004791:Enzyme Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D034741:RNA, Small Interfering; D019275:Radiopharmaceuticals; C426236:ARG tyrosine kinase; D011505:Protein-Tyrosine Kinases