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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

The tyrosine kinase inhibitor PD153035: implication of labeling position on radiometabolites formed in vitro.

INTRODUCTION: The epidermal growth factor receptor is highly expressed in several types of cancers. Molecules with high affinity to its intracellular tyrosine kinase domain are being developed as in vivo imaging probes. The 4-anilinoquinazoline PD153035 has promising in vitro and in vivo properties for development as a reversible radioligand. Labeling it with carbon-11 in either of its two methoxy positions can potentially give rise to different radiometabolites and, consequently, different imaging capabilities. An evaluation of the radiotracers' metabolism was needed to determine the potential significance of the labeling position. METHODS: PD153035 was labeled in the 6- and 7-O-methoxy positions by reacting the corresponding O-desmethyl precursors with [(11)C]methyl iodide. The two radiolabeled compounds were each incubated for 1 h with human and rat liver microsomes. At five time points, the radiolabeled metabolites were examined using radio-liquid chromatography. One metabolite was isolated and subjected to mass spectroscopic analysis. RESULTS: A major polar metabolite was obtained in all incubations. Its molecular weight was consistent with an addition of oxygen, and its fragmentation was consistent with an N-oxidation rather than an aromatic hydroxylation. Regioselective 7-O-dealkylation was also observed, albeit in substantial amounts only in the assay using human microsomes. CONCLUSIONS: Radiolabeling in the 7-O-methoxy position is advocated, since the labeled metabolites produced in the 7-O-demethylation are polar and probably rapidly cleared. The differences observed in the incubations with rat and human microsomes suggest that in vivo positron emission tomography studies with (11)C-labeled PD153035 in rodents may not be directly predictive for studies in humans.[1]


  1. The tyrosine kinase inhibitor PD153035: implication of labeling position on radiometabolites formed in vitro. Sam??n, E., Thorell, J.O., Fredriksson, A., Stone-Elander, S. Nucl. Med. Biol. (2006) [Pubmed]
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