Molecular Imaging of EGFR Kinase Activity in Tumors with 124I-Labeled Small Molecular Tracer and Positron Emission Tomography

Autor: Juri G. Gelovani, David Maxwell, Mikhail Doubrovin, Tatiana Beresten, Ashutosh Pal, Julius Balatoni, Steven M. Larson, Athanasios Glekas, William G. Bornmann, Ronald D. Finn, Mohammad Namavari, Lyudmila Ageyeva, Suren Soghomonyan, Aleksandr Shavrin
Rok vydání: 2006
Předmět:
Models
Molecular
Cancer Research
Iodine Radioisotopes
Mice
Nuclear magnetic resonance
Carcinoma
Non-Small-Cell Lung
Neoplasms
Tumor Cells
Cultured
Tissue Distribution
Epidermal growth factor receptor
Phosphorylation
medicine.diagnostic_test
biology
Brain Neoplasms
Chemistry
Kinase
Protein-Tyrosine Kinases
ErbB Receptors
Oncology
Epidermoid carcinoma
Positron emission tomography
Mice
Nude
Models
Biological
Sensitivity and Specificity
Inhibitory Concentration 50
TRACER
Glioma
Mole
medicine
Animals
Humans
Radiology
Nuclear Medicine and imaging
Radioactive Tracers
Kinase activity
Radionuclide Imaging
Lung cancer
Protein Kinase Inhibitors
Staining and Labeling
business.industry
medicine.disease
Xenograft Model Antitumor Assays
In vitro
Rats
Protein kinase domain
Positron-Emission Tomography
Cancer research
biology.protein
Molecular imaging
K562 Cells
Nuclear medicine
business
Zdroj: Molecular Imaging and Biology. 8:262-277
ISSN: 1860-2002
1536-1632
Popis: Positron emission tomography (PET) with epidermal growth factor receptor (EGFR) kinase-specific radiolabeled tracers could provide the means for noninvasive and repetitive imaging of heterogeneity of EGFR expression and signaling activity in tumors in individual patients before and during therapy with EGFR signaling inhibitors. We developed the synthesis and (124)I-radiolabeling of the (E)-But-2-enedioic acid [4-(3-[(124)I]iodoanilino)-quinazolin-6-yl]-amide-(3-morpholin-4-yl-propyl)-amide (morpholino-[(124)I]-IPQA), which selectively, irreversibly, and covalently binds the adenosine-triphosphate-binding site to the activated (phosphorylated) EGFR kinase, but not to the inactive EGFR kinase. The latter was demonstrated using in silico modeling with crystal structures of the wild type and different gain-of-function mutants of EGFR kinases. Also, this was demonstrated by selective radiolabeling of the EGFR kinase domain with morpholino-[(131)I]-IPQA in A431 human epidermoid carcinoma cells and Western blot autoradiography. In vitro radiotracer accumulation and washout studies demonstrated a rapid accumulation and progressive retention postwashout of morpholino-[(131)I]-IPQA in A431 epidermoid carcinoma and in U87 human glioma cells genetically modified to express the EGFRvIII mutant receptor, but not in the wild-type U87MG glioma cells under serum-starved conditions. Using morpholino-[(124)I]-IPQA, we obtained noninvasive PET images of EGFR activity in A431 subcutaneous tumor xenografts, but not in subcutaneous tumor xenografts grown from K562 human chronic myeloid leukemia cells in immunocompromised rats and mice. Based on these observations, we suggest that PET imaging with morpholino-[(124)I]-IPQA should allow for identification of tumors with high EGFR kinase signaling activity, including brain tumors expressing EGFRvIII mutants and nonsmall-cell lung cancer expressing gain-of-function EGFR kinase mutants. Because of significant hepatobiliary clearance and intestinal reuptake of the morpholino-[(124)I]-IPQA, additional [(124)I]-IPQA derivatives with improved water solubility may be required to optimize the pharmacokinetics of this class of molecular imaging agents.
Databáze: OpenAIRE
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