Molecular imaging of EGFR kinase activity in tumors with (124)I-labeled small molecular tracer and positron emission tomography Journal Article
| Authors: | Pal, A.; Glekas, A.; Doubrovin, M.; Balatoni, J.; Beresten, T.; Maxwell, D.; Soghomonyan, S.; Shavrin, A.; Ageyeva, L.; Finn, R.; Larson, S. M.; Bornmann, W.; Gelovani, J. G. |
| Article Title: | Molecular imaging of EGFR kinase activity in tumors with (124)I-labeled small molecular tracer and positron emission tomography |
| Abstract: | 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 124I-radiolabeling of the (E)-But-2-enedioic acid [4-(3-[ 124I]iodoanilino)-quinazolin-6-yl]-amide- (3-morpholin-4-yl-propyl)-amide (morpholino-[ 124I]-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-[ 131I]-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-[ 131I]-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-[ 124I]-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-[ 124I]-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-[ 124I]-IPQA, additional [ 124I]-IPQA derivatives with improved water solubility may be required to optimize the pharmacokinetics of this class of molecular imaging agents. © Academy of Molecular Imaging 2006. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; squamous cell carcinoma; nonhuman; positron emission tomography; brain tumor; brain neoplasms; sensitivity and specificity; mutant protein; protein domain; neoplasms; mouse; animals; mice; animal tissue; models, biological; lung non small cell cancer; carcinoma, non-small-cell lung; epidermal growth factor receptor; animal experiment; receptor, epidermal growth factor; enzyme activation; in vitro study; tumor xenograft; tumor cells, cultured; xenograft model antitumor assays; enzyme activity; molecular imaging; diagnostic imaging; inhibitor; chronic myeloid leukemia; phosphorylation; protein kinase inhibitors; enzyme phosphorylation; iodine 131; drug distribution; isotope labeling; tissue distribution; iodine radioisotopes; mice, nude; glioma cell; leukemia cell; rat; western blotting; positron-emission tomography; drug tissue level; binding site; crystal structure; models, molecular; iodine 124; radioactive tracers; rats; protein-tyrosine kinases; drug blood level; tracer; adenosine triphosphate; computer model; inhibitory concentration 50; non invasive procedure; quinazoline derivative; carcinoma cell; radionuclide imaging; autoradiography; epidermal growth factor receptor kinase; staining and labeling; drug solubility; k562 cells; cell strain k 562; iodine-124; [4 (3 iodoanilino)quinazolin 6 yl]amide (3 morpholin 4 ylpropyl)amide i 124; but 2 enedioic acid [4 (3 iodoanilino)quinazolin 6 yl]amide (3 morpholin 4 ylpropyl)amide i 124; morpholine derivative |
| Journal Title: | Molecular Imaging and Biology |
| Volume: | 8 |
| Issue: | 5 |
| ISSN: | 1536-1632 |
| Publisher: | Springer |
| Date Published: | 2006-09-01 |
| Start Page: | 262 |
| End Page: | 277 |
| Language: | English |
| DOI: | 10.1007/s11307-006-0049-0 |
| PUBMED: | 16897320 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Erratum/Corrigendum issued, see DOI: 10.1007/s11307-006-0067-y -- "Cited By (since 1996): 67" - "Export Date: 4 June 2012" - "CODEN: CPIMF" - "Source: Scopus" |
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