Radiolabeled Rhein as Small-Molecule Necrosis Avid Agents for Imaging of Necrotic Myocardium

Abstract

A rapid and accurate identification of necrotic myocardium is of great importance for diagnosis, risk stratification, clinical decision-making, and prognosis evaluation of myocardial infarction. Here, we explored technetium-99m labeled rhein derivatives for rapid imaging of the necrotic myocardium. Three hydrazinonicotinic acid-linker-rhein (HYNIC-linker-rhein) derivatives were synthesized, and then, these synthetic compounds were labeled with technetium-99m using ethylenediaminediacetic acid (EDDA) and tricine as coligands [Tc(EDDA)-HYNIC-linker-rhein]. The necrosis avidity of the three Tc-labeled rhein derivatives was tested in a mouse model of ethanol-induced muscular necrosis by gamma counting, histochemical staining, and autoradiography. A lead tracer for visualization of necrotic myocardium was assessed by single photon emission computed tomography/computed tomography (SPECT/CT) imaging in a rat model with reperfused myocardial infarction. The necrosis avidity mechanism of the tracer was explored by DNA binding studies in vitro and blocking experiments in vivo. Results showed that the uptake in necrotic muscles of the threeTc-compounds was higher than that in viable muscles (P < 0.001). Autoradiography and histochemical staining results were consistent with selective uptake of the radiotracer in the necrotic regions. Among the these tracers, Tc(EDDA)-HYNIC-ethylenediamine-rhein [Tc(EDDA)-HYNIC-2C-rhein] displayed the best distribution profiles for imaging. The necrotic myocardium lesions were clearly visualized by SPECT/CT using Tc(EDDA)-HYNIC-2C-rhein at 1 h after injection. The necrotic-to-viable myocardium and necrotic myocardium-to-blood uptake ratios ofTc(EDDA)-HYNIC-2C-rhein were 4.79 and 3.02 at 1 h after injection. DNA binding studies suggested HYNIC-linker-rhein bound to DNA through intercalation. The uptake of Tc(EDDA)-HYNIC-2C-rhein in necrotic muscle was significantly blocked by excessive unlabeled rhein, with 77.61% decline at 1 h after coinjection. These findings suggestedTc(EDDA)-HYNIC-2C-rhein emerged as a "hot spot" imaging probe that has a potential for rapid imaging of necrotic myocardium. The necrosis avidity mechanism of Tc(EDDA)-HYNIC-linker-rhein may be due to its interaction with exposed DNA in necrotic tissues.

Preclinical Evaluation of Radioiodinated Hoechst 33258 for Early Prediction of Tumor Response to Treatment of Vascular-Disrupting Agents

“…In the present study, 131 I-H33258 was shown to have prominent targeting for necrosis in in vivo mouse models with muscle necrosis. Furthermore, statistically significant decreased uptake of 131 I-H33258 in necrotic muscle was observed in the presence of excess cold H33258 compared with the control, which was consistent with our previous research results on other necrosis avid probes [ 33 , 34 ] and suggested that 131 I-H33258 and cold H33258 might share the same specific target in necrotic tissues. In the previous studies, H33258 had been used for delivering imaging group or therapeutic drugs to necrotic tissues by binding to extracellular DNA [ 19 , 30 – 32 ].…”

Updated developments on molecular imaging and therapeutic strategies directed against necrosis

“… HDA SPECT – 67 Shyp SPECT – 68 Hypomycin A SPECT – 69 Rhein SPECT – 70. , 71. 1-hydroxyantha-quinone PET – 72 Naphthazarin SPECT – 73 Vitexin SPECT – 74 Hsp90 GSAO FLI, SPECT – 75.…”

“…4 A) 72 . The in vitro DNA binding studies and in vivo blocking experiments suggested that the necrosis avidity mechanism of 99m Tc(EDDA)-HYNIC-2C-rhein and [ 18 F]FA3OP might be attributable to their interaction with exposed DNA in necrotic tissues 71. , 72.…”

“…1) in rat models of MI (Fig. 4B) 71 . Furthermore, three fluorine-18 labeled 1-hydroxyanthraquinone derivatives were also synthesized and evaluated for their potential to rapidly image necrotic myocardium.…”

Rhein‐based necrosis‐avid MRI contrast agents for early evaluation of tumor response to microwave ablation therapy

“…Fortunately, by splitting the skeleton of hypericin, we found that rhein has excellent necrosis targetability and pharmacokinetic properties . Labeled with 131 I and 99m Tc, rhein‐based probes have been successfully used for imaging necrotic myocardium caused by myocardial infarction. In our previous work, we synthesised 3 Gd 3+ DO3A‐amide MRI contrast agents that were conjugated to rhein through 3 linkers with different lengths: ethylenediamine, 1,4‐butanediamine, and 1,6‐hexanediamine, termed as GdL 1 , GdL 2 , and GdL 3 , respectively (Figure ).…”