| Objective:This study was to evaluate the pharmacokinetics and biodistributionof99mTc-HYNIC-PEG4-E[PEG4-c(RGDfk)]2(99mTc-3PRGD2) in nudemice bearing human esophageal carcinoma xenografts and patientssuffering from esophageal carcinoma, and explore the feasibility ofapplication to clinical imaging. And further discuss the value in clinicalapplications, through the study about SPECT/CT imaging of99mTc-3PRGD2in patients suffering from space occupying disease ofesophagus.Methods:The novel radioactive molecular probe--99mTc-3PRGD2was preparedby freeze-dried kits in which Na99mTcO4solution was added. The maincomposition of the kit was HYNIC-3PRGD2.The quality control wasconducted by radioactive thin layer chromatography (ITLC). Thebiological distribution and SPECT imaging of99mTc-3PRGD2in theEC9706human esophageal squamous carcinoma mice models wereevaluated, which can further provide theoretical basis for applying toclinical tumor imaging.Five volunteers suffering from esophageal carcinoma acceptedSPECT imaging of99mTc-3PRGD2.The safty and effectiveness wereestimated through the study of pharmacokinetics, biological distributionand assessment of radiation dose in patients. After that the study wasprocessed,in which99mTc-3PRGD2was injected in40patients suffering from space occupying disease of esophagus to SPECT/CT imaging.Various analyses were conducted, concluding precision, sensibility andspecificity between barium meal, endoscopy and SPECT/CT imaging; therelationship between radioactive uptake and clinical pathological stage.Meanwhile, the expression of integrin αvβ3was assessed by pathologicaland immunohistochemical methods in normal esophageal tissues andpostoperative esophageal tissues. Correlation analysis between theradioactivity ratio of tumor and non-tumor (T/N) and positive cellpercentage of integrin αvβ3was discussed through the Pearson test. Inconclusion, the diagnosis significance of99mTc-3PRGD2SPECT/CTimaging was evaluated in space occupying disease of esophagus.Results:The labeling yield was over95%by ITLC analysis. The biologicaldistribution results in nude mice bearing human esophageal carcinomaxenografts showed that at0.5,1h,2h and4h after injection99mTc-3PRGD2,the uptake value of99mTc-3PRGD2was (5.17±1.02)%ID/g,(4.76±0.57)%ID/g,(3.71±0.64)%ID/g and (2.42±0.25)%ID/g, higher than all organsin addition to liver and kidney; the ratio of T/N about tumor to blood,heard, lung and muscle came to a head at4h (19.65±3.17,3.40±0.38,2.86±0.27and4.16±0.62, respective). SPECT imaging showed thatradioactive uptake emerged at0.5h after administration, along with thetime the imaging was clearer, and the clearest imaging was obtained at4h.The pharmacokinetics results of five volunteers suffering fromesophageal carcinoma who accepted99mTc-3PRGD2injection showed thatthe radiotracer cleared rapidly in the blood. The radioactive intakepercentage of blood was (42.8±4.0)%at10min,and blood clearanceextended about90%at60min. The fastest excretion of urine radioactivity was within24h, about (43.7±5.2)%. Accumulated a total injection of7-day dose (70.5±7.1)%radionuclide excretion in urine.The biologicaldistribution results in esophageal carcinoma patients showed that thepercentage of intake of the tumor was stepping down in10min(2.63±0.21%),1h (1.78±0.26%) and4h (1.35±0.10%). The ratio of T/Nabout tumor to heart(1.92±0.35),lung(2.04±0.28), thyroid(1.86±0.33),normal esophagus(2.81±0.40) and bone(1.40±0.19) grew to the peak at4h.The SPECT imaging of five patients showed that abnormal radioactiveintake could be found in the place of mass in varying degrees. In the earlystage, the high radioactive background in chest impacted the search of themass. At1h, accumulation of radioactivity in the tumor could be observedmildly, which could be the clearest at4h. The prominent uptake wasemerged in kidney and bladder at all time points, next in liver. The uptakeof gastrointestinal tract was on the high side persistently. The assessmentresult of radiation absorbed dose of the patients displayed: the maximumlie in the kidney (3.53E-02(0.31E-02) mSv/MBq). That of the tumor(6.98E-03(0.36E-03) mSv/MBq) and other major organs showed loweruptake, and the mean absorbed radiation dose of entire body was4.02E-03(0.18E-03)mSv/MBq.32malignant cases and8benign cases were diagnosed by pathologyin40patients who underwent99mTc-3PRGD2SPECT imaging, including31esophageal carcinoma,1leiomyosarcoma,6leimyoma and2esophageal tuberculosis cases. Abnormal accumulation of radioactivitycould be observed in29malignant lesions, and the combined SPECT/CTscan displayed that the region of radioactive uptake and lesions matchedextremely, with the ratio of T/N ranged from1.31to2.79(median2.04). Apulmonary metastasis lesion and a mediastinal lymph node metastasislesion were found in two positive imaging cases.There was no uptake in3 carcinoma cases, presenting false negative imaging；while1tuberculosiscase showed abnormal uptake, presenting false positive imaging. Thediagnosis accurate of barium meal, endoscopy and SPECT/CT imagingwas92.5%,97.5%and90%; the sensibility was93.8%,96.9%and90.6%;specificity was87.5%,100%and87.5%. The sensibility and specificityof SPECT/CT imaging had no statistical significance to the others(P>0.05).99mTc-3PRGD2uptake of the masses had no relevance to thetumor pathologic classification (P>0.05). The immunohistochemicalstaining results showed that integrin αvβ3expressed in the tissues ofesophageal carcinoma and leiomyosarcoma, primarily sepia grain in cellmembrane and cytoplasm. None or only faint yellow grain could be seenin the normal esophageal tissues and the other postoperative esophagealtissues, with statistical significance to malignant disease (P<0.05). Therewas a significant positive correlation between T/N ratio and positive cellpercentage of integrin αvβ3(r=0.976).Conclusion:The novel radiotracer99mTc-3PRGD2could be easily obtained fromfreeze-dried kits with high labeling yield and radiochemical purity. It wasprovided with ideal character of pharmacokinetics and biodistribution andfavorable radiogical safety whether in tumor-bearing mice or inesophageal carcinoma patients.99mTc-3PRGD2SPECT/CT demonstratedcertain clinical value in the diagnosis of esophageal carcinoma anddifferential diagnosis of benign and malignant space occupying lesion. Itscertain superiority of exploring distant metastatic lesion was confirmed.Moreover, there was a significant positive correlation between T/N ratioand positive cell percentage of integrin αvβ3, which further confirmed it'sfeasibility to apply to clinical tumor imaging as integrin αvβ3-positivetumor imaging agent.
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