| Necrosis avid agents(NAAs)show high affinity for necrotic tissues and selectively accumulate in necrotic tissues,radioscintigraphic NAAs could be exploited for "hot spot imaging"of necrotic myocardium to distinguish reversible viable myocardium and irreversible necrotic myocardium,to measure non-viable infarcted areas,to determine the severity,to formulate therapeutic strategies,and to estimate prognosis.Recently,hypericin(Hyp),protohypericin and Sennidin A,which are polyphenolic polycyclic dianthrone compounds,have been recognized as prominent NAAs.As candidate positive tracers for imaging of necrotic myocardium,they showed high imaging contrast between infarcted and viable myocardium after being labeled with radionuclides.However,these dianthrones have poor water solubility,poor stability,and easily forms non-soluble aggregates in an aqueous environment as a result of their big ?-conjugated planar structures,it is also difficult to modify their structure due to the cofacial ?-? stacking between the aromatic cores.Hyp,protohypericin and Sennidin A are composed of coupling two molecules of monomeric anthraquinone in different ways.Based on the evidence that the active center can be found by splitting chemical structure,we speculate that monomeric anthraquinones may be effective functional groups for necrosis targetability,which share simplified structures and shorter plasma half-life times.Moreover,they may possess the potential for assessment of myocardial viability by SPECT/CT imaging of necrotic myocardium at earlier time than Hyp.Therefore,we firstly applied cell binding assays in vitro and mice model of muscular necrosis to investigate the necrosis affinity of eight monomeric anthraquinones with radioiodination.The results indicated that monomeric anthraquinones were a new class of NAAs with simpler structures compared to other recently reported tracers.These novel agents showed prominent targetability to necrotic cells in vitro and necrotic tissues in animal models.Among these NAAs,the necrotic cells uptake of 131I-rhein was 3.47-fold higher than that of the control group,the radioactivity ratios from necrotic to viable muscle of 131I-rhein were 5.84 ± 0.10,7.26± 0.23 and 12.33 ± 0.67 at 2,12 and 24 h after administration,respectively.Additionally,131I-rhein showed the highest necrotic/normal radioactivity ratios,the highest uptake in necrotic muscular and efficient clearance of radioactivity from non-target organs.It is reasonable to speculate that 131I-rhein may possess the potential for early imaging of necrotic myocardium.According to these results,we concluded that monomeric anthraquinones were effective functional groups for necrosis affinity and showed prominent targetability in vitro and in vivo with efficient clearance from normal organs.Hyp is the most studied NAA,however the long plasma half-life time of radio-labelled Hyp with high blood pool activity in vivo would make it unsuitable for early imaging of necrotic myocardium after administration.Although high imaging contrast between infarcted and viable myocardium reached at 9 h after injection,clear visualization of necrotic myocardium was not possible within the clinically relevant time window for thrombolytic therapy(usually within 6 h of the acute event).In this study,131I-rhein showed prominent targetability to necrotic cells or tissues,with highly sustaining necrotic to viable tissues radioactivity ratios and efficient clearance of radioactivity from non-target organs.Thus,we speculated that 131 I-rhein might be more suitable for earlier imaging of necrotic myocardium than 131I-Hyp.Herein we selected I3II-Hyp as a positive control agent and employed rat model of myocardial infarction(MI)to investigate the potential of 131I-rhein for quickly imaging of necrotic myocardium.The results showed that 131I-rhein could visualize necrotic myocardium at 6 h after administration,exhibiting satisfactory heart-to-blood,heart-to-liver and heart-to-lung ratios for achieving images with good quality.By contrast,131I-Hyp failed to present clear imaging of necrotic myocardium at 6 h after injection due to the high uptake in blood,liver and lung that are near the heart,which may compromise the diagnostic capacity.Taken together,it could be concluded that the timing,for visualizing necrotic myocardium with 131I-rhein was earlier than that with 131I-Hyp,and 131I-rhein is a potential agent for early diagnosis of MI.The imaging of necrotic myocardium may enable the assessment of myocardial viability by assuring the proportions of irreversibly infarcted versus jeopardized but still viable viability myocardium.18F-FDG is a gold standard for the evaluation of viability,which is based on segmental differences in perfusion and metabolism to differentiate normal,dysfunctional but viable and necrotic myocardium.However,the results are likely to be false negatives and positives because the uptake of 18F-FDG is easily influenced by the glucose concentration,insulin level and metabolism of individuals.In this study,we used 18F-FDG as a positive control agent,applied rat model of MI to investigate the potential of 131I-rhein for the assessment of myocardial viability by SPECT/CT imaging.The region with low radio-uptake on 18F-FDG-microPCT/CT well matched the region with "hot spot" on SPECT/CT image,the pale necrotic area on TTC staining image and the high radioactivity uptakes of 131I-rhein(in red)on autoradiogram.Meanwhile,SPECT/CT imaging results indicated that 131I-rhein could clearly visualize necrotic myocardium at 3 h after administration and showed highest uptake in necrotic myocardium at 6 h after injection.These results revealed that 131I-rhein possesses the potential for early assessment of myocardial viability by SPECT/CT imaging of necrotic myocardium.In conclusion,monomeric anthraquinones were a new class of NAAs with prominent targetability.131I-rhein possesses the potential for early assessment of myocardial viability by SPECT/CT imaging of necrotic myocardium and is worthy of further research,which will provide a clinical candidate suitable for SPECT/CT or PET/CT imaging of necrotic myocardium to assess myocardial viability. |
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