{"title":"Design and Synthesis of a 18F-Radiolabeled Pyrrolo[2,3-d]pyrimidine Ligand as a CSF1R Receptor PET Imaging Agent","authors":"Srinivasulu Cherukupalli, Morten Karlsen, Bård Helge Hoff, Eirik Sundby","doi":"10.1002/jlcr.4131","DOIUrl":"https://doi.org/10.1002/jlcr.4131","url":null,"abstract":"<div>\u0000 \u0000 <p>Colony-stimulating factor 1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase, is significantly expressed in mononuclear phagocytes and in the central nervous system. It has been identified as a potential drug and imaging target in numerous inflammatory, cancerous, and neurodegenerative diseases. Despite several attempts, no validated CSF1R PET tracer is currently available. Herein, we report the design and synthesis of a <sup>18</sup>F-radiolabeled pyrrolo[2,3-<i>d</i>]pyrimidine molecule based on previously developed potent and selective CSF1R inhibitors. Initially, a nonlabeled fluorinated compound was synthesized using conventional and microwave methods, and it exhibited potent CSF1R inhibitory activity (IC<sub>50</sub> = 6 nM). A tosylate precursor was then synthesized for subsequent radiofluorination. The <sup>18</sup>F-radiolabeled compound was produced using K[<sup>18</sup>F]F Kryptofix 222 (K<sub>2.2.2</sub>)-carbonate in acetonitrile (10% DMF). The optimal labeling conditions, with a tosylate leaving group at 100°C for 5 min, resulted in the production of the <sup>18</sup>F-radiolabeled pyrrolo[2,3-<i>d</i>]pyrimidine CSF1R inhibitor with high purity and with a molar activity of the final product of 57 GBq/μmol. The synthesized inhibitor might open new possibilities for in vivo imaging in neuroinflammation and related disorders, and future studies will evaluate its performance as a PET tracer.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"68 1-2","pages":""},"PeriodicalIF":0.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jie Tong, Baosheng Chen, Tommaso Volpi, Yawen Li, Paul A. Ellison, Zhengxin Cai
{"title":"Current Advances in PARP1-Targeted Theranostics","authors":"Jie Tong, Baosheng Chen, Tommaso Volpi, Yawen Li, Paul A. Ellison, Zhengxin Cai","doi":"10.1002/jlcr.4135","DOIUrl":"https://doi.org/10.1002/jlcr.4135","url":null,"abstract":"<div>\u0000 \u0000 <p>Poly (ADP-ribose) polymerase 1 (PARP1) plays critical roles in DNA repair, chromatin regulation, and cellular equilibrium, positioning it as a pivotal target for therapeutic interventions in cancer and central nervous system (CNS) disorders. PARP1 responds to oxidative stress and DNA damage through PARylation, influencing energy depletion, survival, inflammation, and genomic regulation in many biological scenarios. PARP inhibitors (PARPis) have demonstrated efficacy against cancers harboring defective homologous recombination repair pathways, notably those linked to BRCA mutations. PARP1-targeted PET imaging enables patient stratification, treatment assessment, and PARPi pharmacodynamic evaluation in cancers and other pathophysiological conditions. Importantly, PARP1-targeted theranostics have emerged for both diagnostic imaging and therapeutic applications in multiple types of cancers, representing a pivotal advancement in personalized oncology. However, its application in brain tumors is limited by the heterogeneous integrity of the blood brain barrier (BBB) and the blood-tumor barrier. Thus, the development of BBB-penetrant PARP1 tracers remains an unmet need for imaging brain cancers. This review summarizes the current landscape of radiopharmaceuticals and radioligands targeting PARP1, detailing their pharmacological characteristics and potential clinical uses. Furthermore, this review discusses PARP1 tracers that can cross the BBB, underscoring their potential applications in neurooncology and other neurological disorders.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"68 1-2","pages":""},"PeriodicalIF":0.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gamal Abdelaziz, Ibrahim Y. Abdelghany, Nasser F. Mostafa
{"title":"Evaluation of New-Modelled Recombinant Human Insulin (rh-Insulin) Analog Expressed in E. coli Using Radioiodination Technique Followed by In Vivo Biodistribution in Diabetes-Induced Mice","authors":"Gamal Abdelaziz, Ibrahim Y. Abdelghany, Nasser F. Mostafa","doi":"10.1002/jlcr.4134","DOIUrl":"https://doi.org/10.1002/jlcr.4134","url":null,"abstract":"<div>\u0000 \u0000 <p>Biologists have significantly improved various techniques for confirming the physiological and pharmacological activity of new proteins produced by recombinant DNA technology, such as Western blotting, ELISA, and flow cytometry. Although these methods are costly and comparatively low in efficiency, our study focuses on developing a real-time approach to investigate the physiological activity of our new recombinant human insulin (rh-Insulin), which is expressed in <i>Escherichia coli</i>. An in vivo biodistribution study of radioiodinated rh-Insulin (<sup>125</sup>I-rh-Insulin) was conducted in diabetic-induced mice, exploiting the capability of tyrosine residues in protein molecules to undergo electrophilic substitution of hydrogen atoms with traceable <sup>125</sup>I atoms. We studied many factors to optimize the conditions for the iodination reaction, including the amount of substrate, the amount of chloramine-T, pH, temperature, and reaction time. A high radiochemical yield of 99.01 ± 0.2% was achieved. The in vivo step involved the administration of <sup>125</sup>I-rh-Insulin intravenously (I.V.) in previously induced diabetic mice to study the pharmacokinetics of the new insulin analog. Results show a homogeneous distribution of insulin molecules throughout the body organs, correlating with organ mass, size, and functionality, with no accumulation in distinct organs. The clearance of insulin from the body occurs via both renal and hepatic routes due to the aqueous nature of insulin. Additionally, a parallel experiment was conducted on diabetic mice using only rh-Insulin, resulting in a significant reduction in glucose levels in the mice's blood, thereby exploring the physiological activity of insulin and confirming the ability of our new construct to lower blood glucose levels in diabetic mice. Consequently, this method appears to be much more rapid and effective for the evaluation of biological molecules in vivo using radioactive tracing techniques.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"68 1-2","pages":""},"PeriodicalIF":0.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Synthesis of Carbon 14 and Deuterium-Labelled Nerandomilast (BI 1015550)","authors":"Bachir Latli, Matt J. Hrapchak, Rogelio P. Frutos","doi":"10.1002/jlcr.4133","DOIUrl":"https://doi.org/10.1002/jlcr.4133","url":null,"abstract":"<div>\u0000 \u0000 <p>(<i>R</i>)-2-(4-(5-Chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (<b>BI 1015550, 1</b>) is a potent and selective inhibitor of phosphodiesterase type 4 (PDE4) being developed for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). We report the synthesis of this drug candidate labelled with carbon 14 and deuterium. The carbon 14 synthesis was completed in three radioactive steps in 27% overall yield, with a specific activity of 52 mCi/mmol (1.92 GBq/mmol), radiochemical purity, and enantiomeric excess higher than 99%. The deuterium labelled compound was prepared in seven steps in 67% overall yield and with isotopic enrichment, chemical purity, and enantiomeric excess higher than 99%.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"68 1-2","pages":""},"PeriodicalIF":0.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Towards Optimal Automated 68Ga-Radiolabeling Conditions of the DOTA-Bisphosphonate BPAMD Without Pre-Purification of the Generator Eluate","authors":"Céleste Souche, Juliette Fouillet, Léa Rubira, Charlotte Donzé, Audrey Sallé, Yann Dromard, Emmanuel Deshayes, Cyril Fersing","doi":"10.1002/jlcr.4128","DOIUrl":"10.1002/jlcr.4128","url":null,"abstract":"<p>DOTA-functionalized bisphosphonates can be useful tools for PET imaging of bone metastases when radiolabeled with <sup>68</sup>Ga. Moreover, the versatility of DOTA allows the complexation of radiometals with therapeutic applications (e.g., <sup>177</sup>Lu), positioning these bisphosphonates as attractive theranostic agents. Among these molecules, BPAMD is a compound whose radiolabeling with <sup>68</sup>Ga has already been described, but only through manual methods. Thus, a fully automated protocol for <sup>68</sup>Ga radiolabeling of BPAMD on the GAIA® ± LUNA® synthesis module was designed, and a thorough study of the radiolabeling conditions was undertaken. [<sup>68</sup>Ga]Ga-BPAMD was produced in good radiochemical purity (> 93%) and high radiochemical yield (> 91%) using 0.3 M HEPES buffer. The nature of the reaction vessel showed no significant effect on the radiolabeling outcome. Similarly, addition of an antiradiolysis compound to the reaction medium did not significantly improve the already excellent stability of [<sup>68</sup>Ga]Ga-BPAMD over time. The radiolabeled product obtained by automated synthesis was evaluated in vivo in healthy mice and confirmed high accumulation in the joints and along the backbone.</p>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 14","pages":"441-453"},"PeriodicalIF":0.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11641010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Torben Lund, Niels Jacob Krake, Poul Erik Hansen, Fatima AlZahraa Alatraktchi
{"title":"Simplified Flow Photosynthesis of Deuterium-Labeled Pyocyanin","authors":"Torben Lund, Niels Jacob Krake, Poul Erik Hansen, Fatima AlZahraa Alatraktchi","doi":"10.1002/jlcr.4127","DOIUrl":"10.1002/jlcr.4127","url":null,"abstract":"<div>\u0000 \u0000 <p>Deuterium-labeled pyocyanin was prepared from deuterium-labeled phenazine methosulfate in gram scale by a simplified flow photosynthesis in water. The main product was the protonated red form of pyocyanin-d<sub>3</sub> (Pyo-d<sub>3</sub>-H<sup>+</sup>) in 85 % yield. Quantum chemical calculations of NMR support that nitrogen-10 is protonated. The by-products of the photolysis and the stability of the photolysis mixture were carefully characterized by LC-MS and NMR. Four by-products were identified: An isomer of pyocyanin-d<sub>3</sub> (9%), 8-hydroxypyocyanin-d<sub>3</sub> (4%), 1-hydroxyphenazine (0.4%), and phenazine (1%). The Pyo-d<sub>3</sub>-H<sup>+</sup> product was stable in the photolysis solution after storage at 8°C for 2.5 years. Pure blue pyocyanin-d<sub>3</sub> powder was isolated from the red photolysis solution by the Surrey method in 94 % yield. The addition of the red photolysis solution of Pyo-d<sub>3</sub>-H<sup>+</sup> (100 μM) and commercial pyocyanin (100 μM) to <i>Pseudomonas aeruginosa</i> cultures showed the same growth curves demonstrating that the minor impurities in the photolysis solution do not affect the growth behavior of the bacteria. The protonated deuterium-labeled pyocyanin may be used directly in biological experiments, which make the methodology extremely simple and useful for biologists.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 14","pages":"434-440"},"PeriodicalIF":0.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin R. Edelmann, Filippo Sladojevich, Stephen M. Husbands, Michael B. Otteneder, Ian S. Blagbrough
{"title":"A Brief Review of Radiolabelling Nucleic Acid-Based Molecules for Tracking and Monitoring","authors":"Martin R. Edelmann, Filippo Sladojevich, Stephen M. Husbands, Michael B. Otteneder, Ian S. Blagbrough","doi":"10.1002/jlcr.4126","DOIUrl":"10.1002/jlcr.4126","url":null,"abstract":"<p>The rise of nucleic acid-based therapeutics continues apace. At the same time, the need for radiolabelled oligonucleotides for determination of spatial distribution is increasing. Complex molecular structures with mostly multiple charges and low solubility in organic solvents increase the challenge of integrating radionuclides. In preclinical research, it is important to understand the fate of new drug candidates in biodistribution studies, target binding or biotransformation studies. Depending on a specific question, the selection of a respective radiolabelling strategy is crucial. Radiometals for molecular imaging with positron emission tomography or single-photon computed tomography generally require an attached chelating agent for stable complexation of the metal with the oligonucleotide, whereas labelling using carbon-11/-14 or tritium allows incorporation of the radioisotope into the native structure without altering it. Moreover, the suitability of direct radiolabelling of the oligonucleotide of interest or indirect radiolabelling, for example, by a two-step pretargeting approach, for the study design requires consideration. This review focuses on the challenges of radiolabelling nucleic acid-based molecules with beta-plus, gamma and beta-minus emitters and their use for tracking and monitoring.</p>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 12-13","pages":"410-424"},"PeriodicalIF":0.9,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jlcr.4126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142622239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xingguo Hou, Xiangxing Kong, Yuan Yao, Song Liu, Ya'nan Ren, Muye Hu, Zilei Wang, Hua Zhu, Zhi Yang
{"title":"Next Generation of Solid Target Radionuclide Antibody Conjugates for Tumor Immuno-Therapy","authors":"Xingguo Hou, Xiangxing Kong, Yuan Yao, Song Liu, Ya'nan Ren, Muye Hu, Zilei Wang, Hua Zhu, Zhi Yang","doi":"10.1002/jlcr.4124","DOIUrl":"10.1002/jlcr.4124","url":null,"abstract":"<div>\u0000 \u0000 <p>Immune checkpoint therapy has emerged as an effective treatment option for various types of cancers. Key immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and lymphocyte activation gene 3 (LAG-3), have become pivotal targets in cancer immunotherapy. Antibodies designed to inhibit these molecules have demonstrated significant clinical efficacy. Nevertheless, the ability to monitor changes in the immune status of tumors and predict treatment response remains limited. Conventional methods, such as assessing lymphocytes in peripheral blood or conducting tumor biopsies, are inadequate for providing real-time, spatial information about T-cell distributions within heterogeneous tumors. Positron emission tomography (PET) using T-cell specific probes represents a promising and noninvasive approach to monitor both systemic and intratumoral immune changes during treatment. This technique holds substantial clinical significance and potential utility. In this paper, we review the applications of PET probes that target immune cells in molecular imaging.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 12-13","pages":"396-409"},"PeriodicalIF":0.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yulia A. Vlasenko, Avery J. To, Tess Fortier, Natasha M. Evans, Cole J. Lindsay, Peter J. Palermo, Thorsten Dieckmann, Graham K. Murphy
{"title":"Synthesis and Application of D- and 13C-Labelled tert-Butyl Hoechst Dye","authors":"Yulia A. Vlasenko, Avery J. To, Tess Fortier, Natasha M. Evans, Cole J. Lindsay, Peter J. Palermo, Thorsten Dieckmann, Graham K. Murphy","doi":"10.1002/jlcr.4123","DOIUrl":"10.1002/jlcr.4123","url":null,"abstract":"<p>Herein, the successful syntheses of D<sub>3</sub>- and <sup>13</sup>C-<i>N</i>-methyl and D<sub>9</sub>-<i>tert-</i>butyl Hoechst dyes are presented. This includes the preparation of the labelled D<sub>3</sub>- and <sup>13</sup>C-<i>N-</i>methyl piperazines and D<sub>9</sub>-<i>tert</i>-butylated hydroxytoluene precursors. The <i>tert-</i>butyl Hoechst dye is known to bind a specific RNA aptamer. Spectroscopic NMR studies of the labelled Hoechst dye-aptamer complexes allowed for the unambiguous assignment of chemical shifts, as well as the dynamics of the bound dye.</p>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 12-13","pages":"425-430"},"PeriodicalIF":0.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jlcr.4123","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142502181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shuhua He, Lina Jia, Xiaobei Zheng, Yang Wang, Yuxia Liu, Lan Zhang
{"title":"Preliminary Research of Radiolabeled Atezolizumab for the Noninvasive Evaluation of TNBC PD-L1 Expression In Vivo","authors":"Shuhua He, Lina Jia, Xiaobei Zheng, Yang Wang, Yuxia Liu, Lan Zhang","doi":"10.1002/jlcr.4122","DOIUrl":"10.1002/jlcr.4122","url":null,"abstract":"<div>\u0000 \u0000 <p>Programmed death-ligand 1 (PD-L1) expression is related to the efficacy and prognosis in triple-negative breast cancer. This study employed an indirect labeling method to synthesize [<sup>125</sup>I]PI-Atezolizumab. The in vitro stability of [<sup>125</sup>I]PI-Atezolizumab was assessed through incubation in phosphate buffered saline and fetal bovine serum, revealing sustained stability. Specific binding of [<sup>125</sup>I]PI-Atezolizumab to MDA-MB-231 cells expressing humanized PD-L1 was assessed through in vitro incubation, yielding a <i>K</i><sub>d</sub> value comparable to that of Atezolizumab. This suggests that the labeling process did not compromise the affinity of the Atezolizumab to PD-L1. Subsequently, pharmacokinetic studies were conducted in normal mice and biodistribution experiments in tumor-bearing mice. A comparison of the biodistribution results between [<sup>125</sup>I]PI-Atezolizumab and <sup>125</sup>I-labeled Atezolizumab indicated better in vivo stability for the former. Single photon emission computed tomography (SPECT)/CT imaging further confirmed the targeted specificity of [<sup>125</sup>I]PI-Atezolizumab for PD-L1 in MDA-MB-231 xenografts, which were validated by immunohistochemistry staining. This research underscores the utility of [<sup>125</sup>I]PI-Atezolizumab, prepared via indirect labeling, for monitoring PD-L1 in triple-negative breast cancer models.</p>\u0000 </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"67 11","pages":"384-391"},"PeriodicalIF":0.9,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142108129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}