Discovery of Radioiodinated Monomeric Anthraquinones as a Novel Class of Necrosis Avid Agents for Early Imaging of Necrotic Myocardium

Abstract

Assessment of myocardial viability is deemed necessary to aid in clinical decision making whether to recommend revascularization therapy for patients with myocardial infarction (MI). Dianthraquinones such as hypericin (Hyp) selectively accumulate in necrotic myocardium, but were unsuitable for early imaging after administration to assess myocardial viability. Since dianthraquinones can be composed by coupling two molecules of monomeric anthraquinone and the active center can be found by splitting chemical structure, we propose that monomeric anthraquinones may be effective functional groups for necrosis targetability. In this study, eight radioiodinated monomeric anthraquinones were evaluated as novel necrosis avid agents (NAAs) for imaging of necrotic myocardium. All (131)I-anthraquinones showed high affinity to necrotic tissues and (131)I-rhein emerged as the most promising compound. Infarcts were visualized on SPECT/CT images at 6 h after injection of (131)I-rhein, which was earlier than that with (131)I-Hyp. Moreover, (131)I-rhein showed satisfactory heart-to-blood, heart-to-liver and heart-to-lung ratios for obtaining images of good diagnostic quality. (131)I-rhein was a more promising "hot spot imaging" tracer for earlier visualization of necrotic myocardium than (131)I-Hyp, which supported further development of radiopharmaceuticals based on rhein for SPECT/CT ((123)I and (99m)Tc) or PET/CT imaging ((18)F and (124)I) of myocardial necrosis.

Figure 1. Chemical structures of reference compounds.

Figure 2. Chemical structures of eight monomeric anthraquinones.

Figure 3. HPLC chromatograms of mono-iodorhein or ¹³¹I-rhein.

(a) ultraviolet-chromatogram of mono-iodorhein; (b) radiochemical purity of ¹³¹I-rhein in injection preparation; (c) in vitro stability of ¹³¹I-rhein after 24 h incubation in rat serum at 37 °C.

Figure 4. TTC staining images and autoradiographs of eight tracers from mice sacrificed 24 h after administration.

On the TTC-stained images, the necrotic muscles remained pale whereas normal muscles were stained brick red. The high radioactivity uptakes (in red) primarily appeared in necrotic regions on autoradiograms, which were in accordance with pale areas on TTC staining images. (a–h) were represented ¹³¹I-1-hydroxyanthraquinone, ¹³¹I-alizarin, ¹³¹I-danthron, ¹³¹I-rhein, ¹³¹I-aloe-emodin, ¹³¹I-chrysophanol, ¹³¹I-emodin and ¹³¹I-physcion, respectively.

Figure 5. SPECT/CT imaging of ¹³¹I-rhein or ¹³¹I-Hyp (as a positive control agent) in rats with reperfused MI or sham operation.

SPECT/CT-fused images showed high uptake of ¹³¹I-rhein in the MI and no obviously high radioactivity in viable myocardium, relatively high radioactivity of ¹³¹I-Hyp was observed in heart and liver of model rat or sham operation rat. Red arrows indicate the heart.

Figure 6. Biodistribution and postmortem analyze of MI in rats.

(a) Biodistribution of ¹³¹I-rhein or ¹³¹I-Hyp at 6 h after administration (n = 5 per tracer). Data are expressed as average percentage of injected dose per gram (%ID/g) ± SD: Viable.m = viable myocardium, Necrotic.m = necrotic myocardium; (b–e) Postmortem analyze of necrotic and viable myocardium from model rats of ¹³¹I-rhein: (b) TTC staining image of 2 mm thick slice; (c) autoradiogram from 50 μm frozen section; (d) H&E staining image of 10 μm frozen section; (e) H&E-stained microphotograph proved the presence of necrosis: N = necrotic area, V = viable area.

Figure 7. Synthesis of mono-iodorhein.