Molecular Imaging of EGFR Kinase Activity in Tumors with 124 I-Labeled Small Molecular

摘要: Positron emission tomography (PET) with epidermal growth factor receptor (EGFR) kinasespecific radiolabeled tracers could provide the means for noninvasive and repetitive imaging of heterogeneity EGFR expression signaling activity in tumors individual patients before during therapy inhibitors. We developed synthesis 124 Iradiolabeling (E)-But-2-enedioic acid [4-(3-[ I]iodoanilino)-quinazolin-6-yl]-amide-(3-morpholin-4-yl-propyl)-amide (morpholino-[ I]-IPQA), which selectively, irreversibly, covalently binds adenosine-triphosphate-binding site to activated (phosphorylated) kinase, but not inactive kinase. The latter was demonstrated using silico modeling crystal structures wild type different gain-of-function mutants kinases. Also, this by selective radiolabeling kinase domain morpholino-[ 131 I]-IPQA A431 human epidermoid carcinoma cells Western blot autoradiography. In vitro radiotracer accumulation washout studies a rapid progressive retention postwashout U87 glioma genetically modified express EGFRvIII mutant receptor, wild-type U87MG under serum-starved conditions. Using I]-IPQA, we obtained PET images subcutaneous tumor xenografts, xenografts grown from K562 chronic myeloid leukemia immunocompromised rats mice. Based on these observations, suggest that should allow identification high activity, including brain expressing nonsmall-cell lung cancer mutants. Because significant hepatobiliary clearance intestinal reuptake additional [ derivatives improved water solubility may be required optimize pharmacokinetics class molecular agents.