Synthesis and Preclinical Evaluation of Radioiodinated Hypericin Dicarboxylic Acid as a Necrosis Avid Agent in Rat Models of Induced Hepatic, Muscular, and Myocardial Necroses

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• 作者：Jindian Li ; Jian Zhang ; Shengwei Yang ; Cuihua Jiang ; DongJian Zhang ; Qiaomei Jin ; Qin Wang ; Cong Wang ; Yicheng Ni ; Zhiqi Yin ; Shaoli Song
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：January 4, 2016
• 年：2016
• 卷：13
• 期：1
• 页码：232-240
• 全文大小：447K
• ISSN：1543-8392

文摘

Myocardial infarction (MI) leads to substantial morbidity and mortality around the world. Accurate assessment of myocardial viability is essential to assist therapies and improve patient outcomes. ¹³¹I-hypericin dicarboxylic acid (¹³¹I-HDA) was synthesized and evaluated as a potential diagnostic agent for earlier assessment of myocardium viability compared to its preceding counterpart ¹³¹I-hypericin (¹³¹I-Hyp) with strong hydrophobic property, long plasma half-life, and high uptake in mononuclear phagocyte system (MPS). Herein, HDA was synthesized and characterized, and self-aggregation constant K_α was analyzed by spectrophotometry. Plasma half-life was determined in healthy rats by γ-counting. ¹³¹I-HDA and ¹³¹I-Hyp were prepared with iodogen as oxidant. In vitro necrosis avidity of ¹³¹I-HDA and ¹³¹I-Hyp was evaluated in necrotic cells induced by hyperthermia. Biodistribution was determined in rat models of induced necrosis using γ-counting, autoradiography, and histopathology. Earlier imaging of necrotic myocardium to assess myocardial viability was performed in rat models of reperfused myocardium infarction using single photon emission computed tomography/computed tomography (SPECT/CT). As a result, the self-aggregation constant K_α of HDA was lower than that of Hyp (105602 vs 194644, p < 0.01). ¹³¹I-HDA displayed a shorter blood half-life compared with ¹³¹I-Hyp (9.21 vs 31.20 h, p < 0.01). The necrotic–viable ratio in cells was higher with ¹³¹I-HDA relative to that with ¹³¹I-Hyp (5.48 vs 4.63, p < 0.05). ¹³¹I-HDA showed a higher necrotic–viable myocardium ratio (7.32 vs 3.20, p < 0.01), necrotic myocardium–blood ratio (3.34 vs 1.74, p < 0.05), and necrotic myocardium–lung ratio (3.09 vs 0.61, p < 0.01) compared with ¹³¹I-Hyp. ¹³¹I-HDA achieved imaging of necrotic myocardium at 6 h postinjection (p.i.) with SPECT/CT, earlier than what ¹³¹I-Hyp did. Therefore, ¹³¹I-HDA may serve as a promising necrosis-avid diagnostic agent for earlier imaging of necrotic myocardium compared with ¹³¹I-Hyp. This may support further development of radiopharmaceuticals (¹²³I and ^99mTc) based on HDA for SPECT/CT of necrotic myocardium.