title: Synthesis and Preclinical Evaluation of Radioiodinated Hypericin Dicarboxylic Acid as a Necrosis Avid Agent in Rat Models of Induced Hepatic, Muscular, and Myocardial Necroses.
abstract: 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. (131)I-hypericin dicarboxylic acid ((131)I-HDA) was synthesized and evaluated as a potential diagnostic agent for earlier assessment of myocardium viability compared to its preceding counterpart (131)I-hypericin ((131)I-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 Kα was analyzed by spectrophotometry. Plasma half-life was determined in healthy rats by γ-counting. (131)I-HDA and (131)I-Hyp were prepared with iodogen as oxidant. In vitro necrosis avidity of (131)I-HDA and (131)I-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 Kα of HDA was lower than that of Hyp (105602 vs 194644, p < 0.01). (131)I-HDA displayed a shorter blood half-life compared with (131)I-Hyp (9.21 vs 31.20 h, p < 0.01). The necrotic-viable ratio in cells was higher with (131)I-HDA relative to that with (131)I-Hyp (5.48 vs 4.63, p < 0.05). (131)I-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 (131)I-Hyp. (131)I-HDA achieved imaging of necrotic myocardium at 6 h postinjection (p.i.) with SPECT/CT, earlier than what (131)I-Hyp did. Therefore, (131)I-HDA may serve as a promising necrosis-avid diagnostic agent for earlier imaging of necrotic myocardium compared with (131)I-Hyp. This may support further development of radiopharmaceuticals ((123)I and (99m)Tc) based on HDA for SPECT/CT of necrotic myocardium.
authors.affiliation: Department of Natural Medicinal Chemistry & State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, Jiangsu Province, P. R. China.|Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: Jindian
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: Shengwei
authors.initials: S
authors.lastname: Yang
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: Cuihua
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: DongJian
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: Qiaomei
authors.initials: Q
authors.lastname: Jin
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.|College of Pharmacy, Nanjing University of Chinese Medicine , Nanjing 210023, Jiangsu Province, P. R. China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Natural Medicinal Chemistry & State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, Jiangsu Province, P. R. China.|Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine , Nanjing 210028, Jiangsu Province, P. R. China.|Theragnostic Laboratory, Campus Gasthuisberg, KU Leuven , 3000 Leuven, Belgium.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Natural Medicinal Chemistry & State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, Jiangsu Province, P. R. China.
authors.forename: Zhiqi
authors.initials: Z
authors.lastname: Yin
authors.affiliation: Department of Nuclear Medicine, Renji Hospital, Shanghai Jiaotong University, School of Medicine , Shanghai 200127, P. R. China.
authors.forename: Shaoli
authors.initials: S
authors.lastname: Song
mesh_terms: D000818:Animals; D000873:Anthracenes; D007457:Iodine Radioisotopes / Q000737:chemistry; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects; D009203:Myocardial Infarction / Q000175:diagnosis / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D009336:Necrosis / Q000139:chemically induced*; D010569:Perylene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000873:Anthracenes; D007457:Iodine Radioisotopes; D010569:Perylene; C004965:hypericin
keywords: SPECT/CT; myocardial infarction; necrotic myocardium avidity; radioiodinated hypericin dicarboxylic acid