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Objective:Epidermal growth factor receptor (EGFR) is overexpressed in a wide variety of solid tumors,serving as a well-characterized target for cancer imaging or therapy.In this study,we aimed to design and synthesize a radiotracer,64Cu-NOTA-C225,targeting EGFR for tumor positron emission tomography (PET) imaging.Methods:Cetuximab (C225) was conjugated to a bifunctional chelator,p-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA),and further radiolabeled with copper-64 for PET imaging.64Cu-NOTA-IgG and Cy5.5-C225 were also synthesized as control probes.A431 and A549 mouse models were established for micro-PET and/or near-infrared fluorescence (NIR F) imaging.Results:64Cu-NOTA-C225 exhibited stability in vivo and in vitro up to 24 h and 50 h post-injection,respectively.A431 tumors with average standard uptake values (SUVs) of 5.61±0.69,6.68±1.14,7.80±1.51 at 6,18 and 36 h post-injection,respectively,which were significantly higher than that of moderate EGFR expressing tumors (A549),with SUVs of 0.89±0.16,4.70±0.81,2.01 ±0.50 at 6,18 and 36 h post-injection,respectively.The expression levels of A431 and A549 were confirmed by west blotting.Additionally,the tracer uptake in A431 tumors can be blocked by unlabeled cetuximab,suggesting that tracer uptake by tumors was receptor-mediated.Furthermore,NIRF imaging using Cy5.5-C225 showed that the fluorescence intensity in tumors increased with time,with a maximal intensity of 8.17E+ 10 (p/s/cm2/sr)/(μW/cm2) at 48 h post-injection,which is consistent with the paradigm from micro-PET imaging in A431 tumor-beating mice.Conclusions:The 64Cu-NOTA-C225 PET imaging may be able to specifically and sensitively differentiate tumor models with different EGFR expression levels.It offers potentials as a PET radiotracer for imaging of tracer EGFR-positive tumors.