Novel carbon-11 labeled 4-dimethylamino-but-2-enoic acid [4-(phenylamino)-quinazoline-6-yl]-amides: potential PET bioprobes for molecular imaging of EGFR-positive tumors
Novel carbon-11 labeled 4-dimethylamino-but-2-enoic acid [4-(phenylamino)-quinazoline-6-yl]-amides: potential PET bioprobes for molecular imaging of EGFR-positive tumors
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DOI：
10.1016/j.nucmedbio.2003.12.005
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发表时间：
2004-05-01
影响因子：
3.1
通讯作者：
Shaul, M
中科院分区：
文献类型：
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作者：
Mishani, E;Abourbeh, G;Shaul, M
我们先前已经报道了标记的可逆和不可逆EGFR抑制剂，如4-（3，4-二氯-6-氟苯胺基）-6，7-二甲氧基喹唑啉（ML01）和6-丙烯酰胺基-4-（3，4-二氯-6-氟苯胺基）喹唑啉（ML03），作为成像剂是次优的。在这些研究的基础上，新一代新型的、化学上更稳定的不可逆抑制剂被碳-11标记为潜在的正电子发射断层扫描（PET）生物标志物，用于表皮生长因子受体（EGFR）阳性肿瘤的分子成像。在这些新的标记的不可逆抑制剂中，喹唑啉环6-位上的丙烯酰胺基团被4-二甲基氨基-丁-2-烯酰胺取代。在体外评价未标记的化合物，以确定其EGFR自磷酸化IC50值。IC50值表明，这些新的不可逆化合物对EGFR具有与母体化合物ML03相似的效力。使用公知的标记试剂C-11 Mel，在二甲胺部分用碳-11标记这些化合物。使用商业模块自动化标记程序。最终产物的衰变校正放射化学产率为10%，放射化学纯度为99%，化学纯度为96%，比活度为2.7 Ci/mumol EOB。这些新的标记生物探针对EGFR阳性肿瘤的高效力。(C)2004年爱思唯尔公司All rights reserved.
We have previously reported of labeled reversible and irreversible EGFR inhibitors, such as 4-(3,4-dichloro-6-fluoroanilino)-6,7dimethoxyquinazoline (ML01) and 6-acrylamido-4-(3.4-dichloro-6-fluoroanilino)quinazoline (ML03), to be suboptimal as imaging agents. On the basis of these studies, a new generation of novel, more chemically stable irreversible inhibitors was labeled with carbon-11 as potential positron emission tomography (PET) biomarkers for molecular imaging of epidermal growth factor receptor (EGFR)-positive tumors. In these new labeled, irreversible inhibitors the acryl-amide group at the 6-position of the quinazoline ring was replaced with a 4-dimethylamino-but-2-enoic amide. The nonlabeled compounds were evaluated in vitro to determine their EGFR autophosphorylation IC50 values. The IC50 values indicated that these new irreversible compounds possess similar potencies towards the EGFR, as the parent compound, ML03. These compounds were labeled with carbon-11 at the dimethylamine moiety, using the well known labeling reagent C-11 Mel. The labeling procedure was automated using a commercial module. The final products were obtained with 10% decay corrected radiochemical yield, 99% radiochemical purity, 96% chemical purity, and a high specific activity of 2.7 Ci/mumol EOB. The high potency of these new labeled bioprobes towards the EGFR-positive tumors. (C) 2004 Elsevier Inc. All rights reserved.