Synthesis and Biological Evaluation of Rhein-Based MRI Contrast Agents for in Vivo Visualization of Necrosis.

Early and accurate assessment of therapeutic response to anticancer therapy plays an important role in determining treatment planning and patient management in clinic. Magnetic rseonance imaging (MRI) of necrosis that occurs after cancer therapies provides chances for that. Here, we reported three novel MRI contrast agents, GdL1, GdL2, and GdL3, by conjugating rhein with gadolinium 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]acetic acid (Gd-DOTA) through different linkers. The T1 relaxivities of three probes (7.28, 7.35, and 8.03 mM-1 s-1) were found to be higher than that of Gd-DOTA (4.28 mM-1 s-1). Necrosis avidity of GdL1 was evaluated on the rat models of reperfused liver infarction (RLI) by MRI, which showed an increase of T1-weighted contrast between necrotic and normal liver during 0.5-12 h. Besides, L1 was also labeled with 64Cu to assess its necrosis avidity on rat models of RLI and muscle necrosis (MN) by a γ-counter. The uptakes of 64CuL1 in necrotic liver and muscle were higher than those in normal liver and muscle ( P < 0.05). Then, the ability of GdL1 to assess therapeutic response was tested on rats bearing Walker 256 breast carcinoma injected with a vascular disrupting agent CA4P by MR imaging. The signal intensity of tumoral necrosis was strongly enhanced, and the contrast ratio between necrotic and viable tumor was 1.63 ± 0.11 at 3 h after administration of GdL1. Besides, exposed DNA in necrosis cells may be an important mechanism of three probes targeting to necrosis cells. In summary, GdL1 may serve as a promising MRI contrast agent for accurate assessment of treatment response.

Radioiodinated hypericin disulfonic acid sodium salts as a DNA-binding probe for early imaging of necrotic myocardium.

Necrotic myocardium imaging can provide great indicators of salvaged myocardial areas for clinical guidances to patients with myocardial infarction (MI). One of the key challenges in necrotic myocardium imaging however, is lack of ideal necrotic imaging tracers for exactly and timely depicting the necrotic myocardium. 131I-hypericin (131I-Hyp) is a promising tracer in exact necrotic myocardium delineation. However, it can't clearly image necrotic myocardium until 9h post injection (p.i.) for the high background signals in blood and lung due to the strong lipophilicity. Herein, an optimized 131I-hypericin-2,5-disulfonic acid sodium salts (131I-Shyp) probe was synthesized for better pharmacokinetic and biodistribution properties to necrosis imaging. And the related mechanisms of necrotic avidity ability of 131I-Hyp and 131I-Shyp were also explored. In the results, 131I-Shyp still showed selectively high accumulation in both necrotic cells and tissues. Biodistribution data revealed the decreased uptake of 131I-Shyp in normal organs (lung, spleen and heart) and blood (as shown in pharmacokinetics studies). 131I-Shyp presented quicker and clearer imaging for necrotic myocardium at 4h p.i. compared with 131I-Hyp, suggesting that improved hydrophilicity of 131I-Shyp may be conducive to its better pharmacokinetic and biodistribution properties to imaging. Additionally, DNA competitive binding assays and blocking experiments indicated that E-DNA is the possible target of Shyp and Hyp for their necrosis avidity. 131I-Shyp may serve as a potential E-DNA targeted probe for necrotic myocardium imaging with molecular specificity for clinical use.

Novel 18F-Labeled 1-Hydroxyanthraquinone Derivatives for Necrotic Myocardium Imaging.

Rapid detection and precise evaluation of myocardial viability is necessary to aid in clinical decision making whether to recommend revascularization for patients with myocardial infarction (MI). Three novel 18F-labeled 1-hydroxyanthraquinone derivatives were synthesized, characterized, and evaluated as potential necrosis avid imaging agents for assessment of myocardial viability. Among these tracers, [18F]FA3OP emerged as the most promising compound with best stability and highest targetability. Clear PET images of [18F]FA3OP were obtained in rat model of myocardial infarction and reperfusion at 1 h after injection. In addition, the possible mechanisms of [18F]FA3OP for necrotic myocardium were discussed. The results showed [19F]FA3OP may bind DNA to achieve targetability to necrotic myocardium by intercalation. In summary, [18F]FA3OP was a more promising "hot spot imaging" tracer for rapid visualization of necrotic myocardium.