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

• Published in: Molecular pharmaceutics 2016-01, Vol.13 (1), p.232-240
• Main Authors: Li, Jindian, Zhang, Jian, Yang, Shengwei, Jiang, Cuihua, Zhang, DongJian, Jin, Qiaomei, Wang, Qin, Wang, Cong, Ni, Yicheng, Yin, Zhiqi, Song, Shaoli
• Format: Article
• Language: English
• Subjects: Animals; Iodine Radioisotopes - chemistry; Liver - cytology; Liver - drug effects; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Myocardial Infarction - diagnosis; Myocardial Infarction - metabolism; Myocardium - cytology; Necrosis - chemically induced; Perylene - analogs & derivatives; Perylene - chemistry; Perylene - pharmacology; Rats; Tomography, Emission-Computed, Single-Photon
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.5b00686

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.