摘要
点击化学（Click Chemistry）是由2001年的诺贝尔奖获得者Sharpless教授提出的，它是一种模块化的合成方法，在生物偶联、药物筛选、材料科学等领域得到了广泛的应用。其中的Cu（I）催化的叠氮与炔的1，3-偶极环加成（CuAAC）反应，几乎成了点击化学的代名词。该反应条件温和，对溶剂和pH不敏感，有优越的区域选择性和极高的化学选择性，并且炔基和叠氮基体积小，容易通过亲核反应或亲电反应引入有机物，这些特点顺应了放射性药物，尤其是短半衰期的正电子药物（PET探针）制备中的种种严格要求，因此本研究希望借助点击化学的众多优势，实现对目标分子的标记，建立简单、高效的PET探针制备技术，并通过生物学评价对其进行筛选，探索其临床应用价值。
法尼酯X受体（FXR）在肝再生、肝癌形成、肠道疾病、肠癌形成、胆石病、胆汁淤积和动脉粥样硬化等疾病中扮演着重要角色。因此，本文应用点击化学的标记方法制备评价了一种靶向FXR的胆汁酸类18F-PET探针-18F-CDCA。该PET探针具有较高的标记率（>96%）、放化产率（74±2%，衰变校正）、放化纯度（>99%）和比活度（>320GBq/μmol）。总合成时间（含HPLC纯化时间）为70-80min。18F-CDCA具有良好的体内外稳定性。裸鼠的动态PET/CT显像评价显示肝脏对18F-CDCA摄取迅速，在肝脏几乎均匀分布，并具有适宜的清除时间，这对于肝脏的PET显像极为有利。18F-CDCA在肝脏异常的早期诊断和肿瘤分期中具有重要潜力。
G-蛋白偶联受体（TGR5）是一类位于细胞膜上的胆汁酸受体，在多种肿瘤组织中过量表达，并与患者的预后相关，是肿瘤诊断、治疗和预后评估的一个潜在靶点。因此，本文应用点击化学的标记方法制备评价了一种靶向TGR5的胆汁酸类化合物的18F-PET探针-18F-LCA。该探针具有较高的放化产率（66～74%）、比活度（>300GBq/μmol）和放化纯度（>99%）。18F-LCA具有其母体化合物LCA相似的亲脂性，并具有良好的体外稳定性。本工作为进一步研究18F-LCA作为TGR5过量表达的肿瘤的PET探针奠定了良好的基础。
F-18标记的生物素是基于生物素-亲和素系统（biotin-avidin system，BAS）的预定位PET显像技术的关键，具有高亲和性和低背景吸收等优势。为了克服以往的生物素的F-18标记方法中存在的合成步骤繁琐，制备耗时，放射化学产率低，标记产物不稳定等缺点，本文应用点击化学的方法制备评价了一种新颖的F-18标记的生物素-18F-Biotin。该PET探针制备方便快捷，具有相对较高的放化产率（67±3%，n=3）、比活度（98±2GBq/μmol，n=3）和放化纯度（>99%），总合成时间为75～80min（含HPLC纯化时间），较文献报道的结果均有所改善。18F-Biotin具有良好的亲水性和体外稳定性，无明显的脱氟或降解现象，为该PET探针应用于进一步的体内评价奠定了良好的基础。
本文建立了一种应用一锅法制备多个18F-PET探针以用于对PET探针筛选和临床前研究的策略。具体是以2-[18F]氟叠氮乙烷（[18F]FEA）为Click合成子，反应中以CuSO4/Sodium L-ascorbate为催化体系，在反应体系中同时加入等物质量的几种不同的端炔前体，经过点击化学反应后产物通过一次优化的HPLC分离，即可以在温和条件下一锅制备多个PET探针。若该方法与高通量筛选相结合，有望加速PET探针的发现。
Click chemistry introduced by2001Nobel Laureate K. Barry Sharpless is apowerful modular synthesis approach that has been widely applied inbioconjugation chemistry, drug screening and material science. The copper (I)catalyzed cycloaddition between azides and alkynes (CuAAC) to form1,2,3-triazoles is the most well-known ‘click reaction’ and nearly becamesynonymous with the concept of click chemistry. The click reaction meets theneed for requirements in the preparation of radiopharmaceuticals, especially forradiopharmaceuticals with short half-life nuclides (e.g. PET probes) because ofits mild reaction conditions, tolerance of solvents and pH, high chemoselectivityand perfect regioselectivity, meanwhile, azide and alkyne groups are small insize and easy to be introduced into organic compounds by both nucleophilic andelectrophilic processes. Therefore, this paper aimed for radiolabeing of targetmolecules with the advantages of click chemistry and developing simple andefficient preparation techniques of PET probes. Furthermore, the screening ofPET probes was conducted through biological evaluation for the investigation oftheir clinical value.
The farnesoid-X-receptor (FXR) plays important roles in liver regeneration,liver tumorigenesis, intestinal diseases, intestinal tumorigenesis, gallstonedisease, cholestasis, and atherosclerosis. Therefore, the PET probe18F-CDCAtargeting FXR which was an18F-labeled bile acid compound was synthesizedwith the click chemistry and biologically evaluated. The PET probe showed ahigh radiolabeling yield (>96%), high decay-corrected radiochemical yield (74±2%), high radiochemical purity (>99%), and high specific activity (>320GBq/μmol) and the overall synthesis time, including HPLC purification, was70-80min.18F-CDCA had a high metabolic stability in vitro and in vivo. PETimaging studies in nude mice indicated a rapid uptake of18F-CDCA into livertissue with uniform distribution of radioactivity and a suitable clearance time in the liver which was beneficial for PET imaging in the liver. Thus, it is potentialfor early detection of abnormalities in the liver and staging of neoplasms with18F-CDCA.
G protein-coupled receptor (TGR5) is a cell-surface bile acid receptor whichis a potential target for diagnosis, treatment and prognosis evaluation of thetumors, whose expression is strongly upregulated in many tumors compared toexpression levels in normal tissues and is associated with the prognosis of thepatients. Therefore, the18F-PET probe18F-LCA was prepared and evaluatedusing the click chemistry method with a high radiochemical yield (66～74%),high radiochemical purity (>99%), and high specific activity (>300GBq/μmol).18F-LCA had a similar lipophilicity to the parental bile acid lithocholic acid anda high metabolic stability in vitro. This work made a solid foundation for furtherstudy the18F-LCA as the PET probe for the tumors of TGR5-overexpression.
F-18labeled biotin was the key of pretargeting PET imaging based onbiotin-avidin system (BAS) with higher binding affinity and lower backgroundactivity. In order to overcome the disadvantages of tedious multi-step procedure,time-consuming preparation, low radiochemical yield and instability ofradiolabeling product as previous reports, the18F-labeled biotin was preparedand evaluated with the click chemistry method. It’s convenient and efficient tosynthesize18F-biotin with a high radiochemical yield (67±3%), and high specificactivity (98±2GBq/μmol), high radiochemical purity (>99%) and the overallsynthesis time, including HPLC purification, was75-80min, which wereimproved compared with previous reports.18F-biotin had good hydrophilicityand good stability in vitro, defluorination or radiometabolites were not detectedafter long-term incubation, which provided good foundation for further study invivo.
A novel strategy for labeling multiple18F-PET probes in one pot has beendeveloped for PET probes screening and preclinical studies. In this study,2-[18F]fluoroethylazide was selected as the prosthetic group, CuSO4/Sodium L-ascorbate was selected as the catalytic system. It simply requires the additionof equal amount of multiple terminal alkynyl precursors to the click reactionsystem, and then multiple PET probes could be prepared in one pot under mildreaction conditions after separation with appropriate HPLC gradients in a singlerun. If combined with high throughout screening, the discovery ofhigh-efficiency PET probes may be accelerated.
引文
[1]李林法,张敏鸣.肿瘤靶向分子影像[M].北京:科学出版社,2006:204-259.
[2]王荣福. PET/CT—分子影像学新技术应用[M].第一版.北京：北京大学医学出版社，2011:8-30.
[3] Lambrecht M, Haustermans K. Clinical evidence on PET-CT for radiationtherapy planning in gastro-intestinal tumors[J]. Radiother Oncol,2010,96(3):339-346.
[4] Dauwen H, Van Calster B, Deroose C M, et al. PET/CT in the staging of patientswith a pelvic mass suspicious for ovarian cancer[J]. Gynecol Oncol,2013,131(3):694-700.
[5] Fularz M, Adamiak P, Czepczynski R, et al. Positron emission tomography (PET)in malignant ovarian tumors[J]. Ginekol Pol,2013,84(8):720-725.
[6] Song M J, Bae S H, Lee S W, et al. F-18-Fluorodeoxyglucose PET/CT predictstumour progression after transarterial chemoembolization in hepatocellularcarcinoma[J]. Eur J Nucl Med Mol Imaging,2013,40(6):865-873.
[7] Pimlott S L, Sutherland A. Molecular tracers for the PET and SPECT imaging ofdisease [J]. Chem Soc Rev,2011,40(1):149-162.
[8] Fletcher J W, Djulbegovic B, Soares H P, et al. Recommendations on the Use of18F-FDG PET in Oncology[J]. J Nucl Med,2008,49(3):480-508.
[9] Ganapathy V, Thangaraju M, Prasad P D. Nutrient transporters in cancer:Relevance to Warburg hypothesis and beyond[J]. Pharmacol Thera,2009,121(1):29-40.
[10] Palacin M, Estevez R, Bertran J, et al. Molecular biology of mammalian plasmamembrane amino acid transporters[J]. Physiol Rev,1998,78(4):969-1054.
[11] McConathy J, Yu W, Jarkas N, et al. Radiohalogenate d nonnatural amino acidsas PET and SPECT tumor imaging agents[J]. Med Res Rev,2011,32(4):868-905.
[12] Smolen M, Kaczmarek A, Bisikiewicz E, et al. One-day study protocol for18F-FET and18F-FDG PET/CT imaging of brain tumours[J]. Eur J Nucl Med MolImaging,2011,38(S2): S444-S444.
[13] Kaira K, Oriuchi N, Yanagitani N, et al. Assessment of Therapy Response inLung Cancer With F-18-alpha-Methyl Tyrosine PET[J]. Am J Roentgenol,2010,195(5),1204-1211.
[14] Lizarraga K J, Allen-Auerbach M, Czernin J, et al. F-18-FDOPA PET forDifferentiating Recurrent or Progressive Brain Metastatic Tumors from Late orDelayed Radiation Injury After Radiation Treatment[J]. J Nucl Med,2014,55(1):30-36.
[15] Hustinx R, Lemaire C, Jerusalem G, et al. Whole-Body Tumor Imaging UsingPET and2-18F-Fluoro-L-Tyrosine: Preliminary Evaluation and Comparison with18F-FDG[J]. J Nucl Med,2003,44(4):533-539.
[16] Yu W, Williams L, Camp V, et al. Synthesis and biological evaluation ofanti-1-amino-2-[18F]fluoro-cyclobutyl-1-carboxylic acid (anti-2-[18F]FACBC) in rat9L gliosarcoma[J]. Bioorg Med Chem Lett,2010,20(7):2140-2143.
[17] Langen K J, Hamacher K, Weckesser M, et al. O-(2-[18F]fluoroethyl)-L-tyrosine:uptake mechanisms and clinical applications[J]. Nucl Med Biol,2006,33(3):287-294.
[18] Piroth M D, Pinkawa M, Holy R, et al. Prognostic value of early[18F]fluoroethyltyrosine positron emission tomography after radiochemotherapy inglioblastoma multiforme[J]. Int J Radiat Oncol Biol Phys,2011,80(1):176-184.
[19] Piroth M D, Holy R, Pinkawa M, et al. Prognostic impact of postoperative,pre-irradiation18F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated withradiochemotherapy[J]. Radiother Oncol,2011,99(2):218-224.
[20] Mueller D, Klette I, Kalb F, et al. Synthesis of O-(2-[18F]fluoroethyl)-L-tyrosinebased on a cartridge purification method[J]. Nucl Med Biol2011,38(5):653-658.
[21] Lee T S, Ahn S H, Moon B S, et al. Comparison of18FFDG,18F-FET and18F-FLT for differentiation between tumor and inflammation in rats[J]. Nucl MedBiol,2009,36(6):681-686.
[22] Rau F C, Weber W A, Wester H J, et al. O-(2-[18F]Fluoroethyl)-L-tyrosine(FET): a tracer for differentiation of tumour from inflammation in murine lymphnodes[J]. Eur J Nucl Med Mol Imaging,2002,29(8):1039-1046.
[23] Stadlbauer A, Prante O, Nimsky C, et al. Metabolic imaging of cerebral gliomas:spatial correlation of changes in O-(2-18Ffluoroethyl)-L-tyrosine PET and protonmagnetic resonance spectroscopic imaging[J]. J Nucl Med,2008,49(5):721-729.
[24] Galldiks N, Rapp M, Stoffels G, et al. Response assessment of bevacizumab inpatients with recurrent malignant glioma using F-18Fluoroethyl-l-tyrosine PET incomparison to MRI[J]. Eur J Nucl Med Mol Imaging,2013,40(1):22-33.
[25] Beuthien-Baumann B, Bredow J, Burchert W, et al.3-O-Methyl-6-F-18fluoro-L-DOPA and its evaluation in brain tumour imaging[J]. Eur J Nucl Med MolImaging,2003,30(7):1004-1008.
[26] Hoegerle S, Ghanem N, Altehoefer C, et al. F-18-DOPA positron emissiontomography for the detection of glomus tumours[J]. Eur J Nucl Med Mol Imaging,2003,30(5):689-694.
[27] Chen W, Silverman D H S, Delaloye S, et al. F-18-FDOPA PET imaging ofbrain tumors: Comparison study with F-18-FDG PET and evaluation of diagnosticaccuracy[J]. J Nucl Med,2006,47(6):904-911.
[28] McConathy J, Voll R J, Yu W, et al. Improved synthesis of anti-[18F]FACBC:improved preparation of labeling precursor and automated radiosynthesis[J]. ApplRadiat Isot,2003,58:657-666.
[29] Schuster D, Votaw J, Halkar R, et al. Uptake of the synthetic pet amino acidradiotracer1-amino-3-[18F] fluorocyclobutane-1-carboxylic acid (18F-FACBC)within primary and metastatic brain cancer compared with18F-fluorodeoxyglucose(18F-FDG)[J]. J Nucl Med,2003,44(5):167.
[30] Shoup T M, Olson J, Hoffman J M, et al. Synthesis and evaluation of[18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors[J]. JNucl Med,1999,40(2):331-338.
[31] Oka S, Hattori R, Kurosaki F, et al. A preliminary study ofanti-1-amino-3-18Ffluorocyclobutyl-1-carboxylic acid for the detection of prostateCancer[J]. J Nucl Med,2007,48(1):46-55.
[32] Schuster D M, Votaw J R, Nieh P T, et al. Initial experience with the radiotraceranti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostatecarcinoma[J]. J Nucl Med,2007,48(1):56-63.
[33] McConathy J, Martarello L, Malveaux E J, et al. Radiolabeled amino acids fortumor imaging with PET: radiosynthesis and biological evaluation of2-amino-3-[18F]fluoro-2-methylpropanoic acid and3-[18F]fluoro-2-methyl-2-(methylamino) propanoic acid[J]. J Med Chem,2002,45(11):2240-2249.
[34] Chiotellis A, Mu L J, Muller A, et al. Synthesis and biological evaluation ofF-18-labeled fluoropropyl tryptophan analogs as potential PET probes for tumorimaging[J]. Eur J Med Chem,2013,70:768-780.
[35] Podo F. Tumour phospholipid metabolism[J]. NMR Biomed,1999,12(7):413-439.
[36] Tedeschi G, Lundbom N, Raman R, et al. Increased choline signal coincidingwith malignant degeneration of cerebral gliomas: a serial proton magnetic resonancespectroscopy imaging study[J]. J Neurosurg,1997,87(4):516-524.
[37] Awwad, H M, Geisel J, Obeid R. The role of choline in prostate cancer[J]. ClinBiochem,2012,45(18):1548-1553.
[38] Glunde K, Ackerstaff E, Mori N, et al. Choline phospholipid metabolism incancer: Consequences for molecular pharmaceutical interventions[J]. Mol Pharm,2006,3(5):496-506.
[39] Shah T, Wildes F, Penet M F, et al. Choline kinase overexpression increasesinvasiveness and drug resistance of human breast cancer cells[J]. NMR Biomed,2010,23(6):633-642.
[40] Glunde K, Bhujwalla ZM, Ronen SM. Choline metabolism in malignanttransformation[J]. Nat Rev Cancer,2011,11(12):835-848.
[41] Glunde K, Jiang L, Moestue S A, et al. MRS and MRSI guidance in molecularmedicine: targeting and monitoring of choline and glucose metabolism in cancer[J].Nmr in Biomedicine,2011,24(6):673-690.
[42] Hara T.18F-fluorocholine: a new oncologic PET tracer[J]. J Nucl Med,2001,42(12):1815-1816.
[43] Ito K, Yokoyama J, Kubota K, et al.18F-FDG versus11C-choline PET/CT forthe imaging of advanced head and neck cancer after combined intraarterialchemotherapy and radiotherapy: the time period during which PET/CT can reliablydetect non-recurrence[J]. Eur J Nucl Med Mol Imaging,2010,37(7):1318-1327.
[44] Hara T.11C-choline and2-deoxy-2-[18F]fluoro-D-glucose in tumor imaging withpositron emission tomography[J]. Mol Imaging Biol,2002,4(4):267-273.
[45] Hara T, Yuasa M. Automated synthesis of fluorine-18labeled choline analog:2-fluoroethyl-dimethyl-2-oxyethylammonium[J]. J Nucl Med,1997,38(Suppl):44P.
[46] DeGrado T R, Baldwin S W, Wang S, et al. Synthesis and evaluation of18F-labeled choline analogs as oncologic PET tracers[J]. J Nucl Med2001,42(12):1805-1814.
[47] Hara T, Kondo T, Hara T, et al. Use of18F-choline and11C-choline as contrastagents in positron emission tomography imaging-guided stereotactic biopsysampling of gliomas[J]. J Neurosurg,2003,99(3):474-479.
[48] Balogova S, Huchet V, Kerrou K, et al. Detection of bronchioloalveolar cancerby means of PET/CT and18F-fluorocholine, and comparison with18F-fluorodeoxyglucose[J]. Nucl Med Commun,2010,31(5):389-397.
[49] Talbot J N, Fartoux L, Balogova S, et al. Detection of hepatocellular carcinomawith PET/CT: a prospective comparison of18F-fluorocholine and18F-FDG inpatients with cirrhosis or chronic liver disease[J]. J Nucl Med,2010,51(11):1699-1706.
[50] van den Esschert J W, Bieze M, Beuers U H, et al. Differentiation ofhepatocellular adenoma and focal nodular hyperplasia using18F-fluorocholinePET/CT[J]. Eur J Nucl Med Mol Imaging,2011,38(3):436-440.
[51] Schwarzenbock S, Souvatzoglou M, Krause B J. Choline PET and PET/CT inPrimary Diagnosis and Staging of Prostate Cancer[J]. Theranostics,2012,2(3):318-330.
[52] Chiti A, Picchio M. The rising PET: the increasing use of choline PET/CT inprostate cancer[J]. Eur J Nucl Med Mol Imaging,2011,38(1),53-54.
[53] Hara T, Kosaka N, Kishi H. Development of18F-fluoroethylcholine for cancerimaging with PET: synthesis, biochemistry, and prostate cancer imaging[J]. J NuclMed,2002,43(2):187-199.
[54] Price D T, Coleman R E, Liao R P, et al. Comparison of [18F]fluorocholine and
[18F]fluorodeoxyglucose for positron emission tomography of androgen dependentand androgen independent prostate cancer[J]. J Urol,2002,168(1):273-280.
[55] Kwee S A, Coel M N, Lim J, et al. Prostate cancer localization with18fluorinefluorocholine positron emission tomography[J]. J Urol,2005,173(1):252-255.
[56] Husarik D B, Miralbell R, Dubs M, et al. Evaluation of [18F]-choline PET/CTfor staging and restaging of prostate cancer[J]. Eur J Nucl Med Mol Imaging,2008,35(2):253-263.
[57] Kwee S A, Thibault G P, Stack R S, et al. Use of step-section histopathology toevaluate18Ffluorocholine PET sextant localization of prostate cancer[J]. MolImaging,2008,7(1):12-20.
[58] Igerc I, Kohlfurst S, Gallowitsch H J, et al. The value of18F-choline PET/CT inpatients with elevated PSA-level and negative prostate needle biopsy for localizationof prostate cancer[J]. Eur J Nucl Med Mol Imaging,2008,35(5):976-983.
[59] Martin S, Eisenbarth J, Wagner-Utermann U, et al.[18F]FLT:18F labeling of3-Boc-1-(2-deoxy-3-O-nosyl-5-O-trityl-b-Dlyxofuranosyl) thymine and otherthymine derivatives[J]. J Nucl Med,2000,41(5): S255.
[60] Martin S, Eisenbarth J, Wagner-Utermann U, et al. A new precursor for theradiosynthesis of [18F]FLT[J]. Nucl Med Biol,2002,29(2):263-273.
[61] Been L B, Suurmeijer A J, Cobben D C, et al.[18F]FLT-PET in oncology:current status and opportunities[J]. Eur J Nucl Med Mol Imaging,2004,31(12):1659-1672.
[62] Vesselle H, Grierson J, Peterson L M, et al.18F-fluorothymidine radiationdosimetry in human PET imaging studies[J]. J Nucl Med,2003,44(9):1482-1488.
[63] Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumorswith18F-FLT PET: comparision with18FFDG[J]. J Nucl Med,2005,46(6):945-952.
[64] Miyake K, Shinomiya A, Okada M, et al. Usefulness of FDG, MET andFLT-PET studies for the management of human gliomas[J]. J Biomed Biotechnol2012:205818, doi:10.1155/2012/205818.
[65] Buck A K, Schirrmeister H, Hetzel M, et al.3-Deoxy-3-[18F]fluorothymidinepositron emission tomography for noninvasive assessment of proliferation inpulmonary nodules[J]. Cancer Res,2002,62(12):3331-3334.
[66] Yang W F, Zhang Y M, Fu Z, et al. Imaging proliferation of F-18-FLT PET/CTcorrelated with the expression of microvessel density of tumour tissue innon-small-cell lung cancer[J]. Eur J Nucl Med Mol Imaging,2012,39(8):1289-1296.
[67] Wu C Y, Chou L S, Chan P C, et al. Monitoring Tumor Response withRadiolabeled Nucleoside Analogs in a Hepatoma-Bearing Mouse Model Early AfterDoxisome○R Treatment[J]. Mol Imaging Biol,2013,15(3):326-335.
[68] Li Z B, Cai H C, Conti P S. Improved synthesis of2cent-deoxy-2cent-F-18fluoro-5-methyl-1-b-D-arabinofuranosyluracil (F-18-FMAU)[J]. Abstracts of Papersof the American Chemical Society,2010,240,43-NUCL.
[69] Paolillo V, Riese S, Gelovani J G, et al. A fully automated synthesis of F-18-FEAU and F-18-FMAU using a novel dual reactor radiosynthesis module[J]. JLabel Compd Radiopharm,2009,52(13-14):553-558.
[70] Turkman N, Gelovani J G, Alauddin M M. A novel method for stereospecificfluorination at the2'-arabino-position of pyrimidine nucleoside: synthesis of F-18-FMAU[J]. J Label Compd Radiopharm,2010,53(13-14):782-786.
[71] Jadvar H, Yap L P, Park R, et al. F-18-2'-Fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (F-18-FMAU) in Prostate Cancer: Initial PreclinicalObservations[J]. Mol Imaging,2012,11(5):426-432.
[72] Nishii R, Volgin A Y, Mawlawi O, et al. Evaluation of2’-deoxy-2’-F-18fluoro-5-methyl-1-beta-L-arabinofuranosyluracil (F-18-L-FMAU) as a PET imagingagent for cellular proliferation: comparison with F-18-D-FMAU and F-18FLT[J].Eur J Nucl Med Mol Imaging,2008,35(5):990-998.
[73] Chan P C, Wu C Y, Chang W T, et al. Monitoring tumor response with F-18FMAU in a sarcoma-bearing mouse model after liposomal vinorelbine treatment[J].Nucl Med Biol,2013,40(8):1035-1042.
[74] Tehrani O S, Muzik O, Heilbrun L K, et al. Tumor imaging using1-(2-deoxy-2’-18F-fluoro-beta-D-arabinofuranosyl)thymine and PET[J]. J Nucl Med,2007,48(9):1436-1441.
[75] Sun H, Sloan A, Mangner T J, et al. Imaging DNA synthesis with [18F]FMAUand positron emission tomography in patients with cancer[J]. Eur J Nucl Med MolImaging,2005,32(1):15-22.
[76] Smith G, Sala R, Carroll L, et al. Synthesis and evaluation of nucleosideradiotracers for imaging proliferation[J]. Nucl Med Biol,2012,39(5):652-665.
[77] Reichlin S. SOMATOSTATIN.1[J]. N Engl J Med,1983,309(24):1495-1501.
[78] Reichlin S. SOMATOSTATIN.2[J]. N Engl J Med,1983,309(25),1556-1563.
[79] Schulz S, Schmitt J, Quednow C, et al. Immunohistochemical detection ofsomatostatin receptors in human ovarian tumors[J]. Gynecol Oncol,2002,84(2):235-240.
[80] Jenkins S A, Kynaston H G, Davies N, et al. Somatostatin analogs in oncology:A look to the future[J]. Chemotherapy,2001,47(S2):162-196.
[81] Kogner P, Borgstrom P, Bjellerup P, et al. Somatostatin in neuroblastoma andganglioneuroma[J]. Eur J Cancer,1997,33(12):2084-2089.
[82] Rufini V, Calcagni M L, Baum R P. Imaging of neuroendocrine tumors[J].Semin Nucl Med,2006,36(3):228-247.
[83] Guhlke S, Wester H J, Bruns C, et al.2-[18F]fluoropropionyl-DPhe1-octreotide,a potential radiopharmaceutical for quantitative somatostatin receptor imaging withPET: synthesis, radiolabeling, in vitro validation and biodistribution in mice[J]. NuclMed Biol,1994,21(6):819-825.
[84] Wester H J, Brockmann J, Rosch F, et al. PET-pharmacokinetics of18F-octreotide: a comparison with67Ga-DFO-and86Y-DTPA-octreotide[J]. NuclMed Biol,1997,24(4):275-286.
[85] Wester H J, Schottelius M, Scheidhauer K, et al. PET imaging of somatostatinreceptors: design, synthesis and preclinical evaluation of a novel18F-labelled,carbohydrated analogue of octreotide[J]. Eur J Nucl Med Mol Imaging,2003,30(1):117-122.
[86] Meisetschlager G, Poethko T, Stahl A, et al. Gluc-Lys(F-18FP)-TOCA PET inpatients with SSTR-positive tumors: Biodistribution and diagnostic evaluationcompared with In-111DTPA-octreotide[J]. J Nucl Med,2006,47(4):566-573.
[87] Schottelius M, Wester H J, Reubi J C, et al. Improvement of pharmacokineticsof radioiodinated Tyr(3)-octreotide by conjugation with carbohydrates[J]. BioconjugChem,2002,13(5):1021-1030.
[88] Schirrmacher R, Bradtmoller G, Schirrmacher E, et al. F-18-labeling of peptidesby means of an organosilicon-based fluoride acceptor[J]. Angew Chem Int Edit,2006,45(36):6047-6050.
[89] Wangler C, Waser B, Alke A, et al. One-Step F-18-Labeling of Carbohydrate-Conjugated Octreotate-Derivatives Containing a Silicon-Fluoride-Acceptor (SiFA):In Vitro and in Vivo Evaluation as Tumor Imaging Agents for Positron EmissionTomography (PET)[J]. Bioconjugate Chem,2010,21(12):2289-2296.
[90] Laverman P, McBride W J, Sharkey R M, et al. A Novel Facile Method ofLabeling Octreotide With18F-Fluorine[J]. J Nucl Med,2010,51(3):454-461.
[91] McBride W J, D'Souza C A, Sharkey R M, et al. Improved F-18Labeling ofPeptides with a Fluoride-Aluminum-Chelate Complex[J]. Bioconjugate Chem,2010,21(7):1331-1340.
[92] Iddon L, Leyton J, Indrevoll B, et al. Synthesis and in vitro evaluation of F-18fluoroethyl triazole labelled Tyr(3) octreotate analogues using click chemistry[J].Bioorg Med Chem Lett,2011,21(10):3122-3127.
[93] Leyton J, Iddon L, Perumal M, et al. Targeting Somatostatin Receptors:Preclinical Evaluation of Novel F-18-Fluoroethyltriazole-Tyr(3)-Octreotate Analogsfor PET[J]. J Nucl Med,2011,52(9):1441-1448.
[94] Ishihara T, Shigemoto R, Mori K, et al. FUNCTIONAL EXPRESSION ANDTISSUE DISTRIBUTION OF A NOVEL RECEPTOR FOR VASOACTIVEINTESTINAL POLYPEPTIDE[J]. Neuron,1992,8(4):811-819.
[95] Szilasi M, Buglyo A, Treszl A, et al. Gene expression of vasoactive intestinalpeptide receptors in human lung cancer[J]. Int J Oncol,2011,39(4):1019-1024.
[96] Fernandez-Martinez A B, Carmena M J, Arenas M I, et al. Overexpression ofvasoactive intestinal peptide receptors and cyclooxygenase-2in human prostatecancer. Analysis of potential prognostic relevance[J]. Histol Histopath,2012,27(8):1093-1101.
[97] Vacas E, Bajo A M, Schally A V, et al. Antioxidant activity of vasoactiveintestinal peptide in HK2human renal cells[J]. Peptides,2012,38(2):275-281.
[98] Vacas E, Fernandez-Martinez A B, Bajo A M, et al. Vasoactive intestinal peptide(VIP) inhibits human renal cell carcinoma proliferation[J]. Biochim BiophysActa-Mol Cell Res,2012,1823(10):1676-1685.
[99] Moody T W and Gozes I. Vasoactive intestinal peptide receptors: a moleculartarget in breast and lung cancer[J]. Curr Pharm Des,2007,13(11):1099-1104.
[100] Reubi J C, L derach U, Waser B, et al. Vasoactive intestinal peptide/pituitaryadenylate cyclase-activating peptide receptor subtypes in human tumors and theirtissues of origin[J]. Cancer Res,2000,60(11):3105-3112.
[101] Thakur M L, Aruva M R, Gariepy J, et al. PET imaging of oncogeneoverexpression using Cu-64-vasoactive intestinal peptide (VIP) analog: Comparisonwith Tc-99m-VIP analog[J]. J Nucl Med,2004,45(8):1381-1389.
[102] Rangger C, Helbok A, Ocak M, et al. Design and Evaluation of NovelRadiolabelled VIP Derivatives for Tumour Targeting[J]. Anticancer Res,2013,33(4):1537-1546.
[103] Cheng D F, Yin D Z, Li G C, et al. Radiolabeling and in vitro and in vivocharacterization of F-18FB-R-8,R-15,R-21, L-17-VIP as a PET imaging agent fortumor overexpressed VIP receptors[J]. Chem Biol Drug Des,2006,68(6):319-325.
[104] Cheng D F, Yin D Z, Zhang L, et al. Preparation of the novelfluorine-18-labeled VIP analog for PET imaging studies using two differentsynthesis methods[J]. J Fluor Chem,2007,128(3):196-201.
[105] Cheng D F, Liu Y X, Shen H, et al. F-18Labeled Vasoactive Intestinal PeptideAnalogue in the PET Imaging of Colon Carcinoma in Nude Mice[J]. BiomedResearch International,2013.
[106] Wieduwilt M J and Moasser M M. The epidermal growth factor receptorfamily: biology driving targeted therapeutics[J]. Cell Mol Life Sci,2008,65(10):1566-1584.
[107] Dassonville O, Bozec A, Fischel J L, et al. EGFR targeting therapies:monoclonal antibodies versus tyrosine kinase inhibitors. Similarities anddifferences[J]. Crit Rev Oncol Hematol,2007,62(1):53-61.
[108] Ciardiello F, Tortora G. EGFR antagonists in cancer treatment[J]. N Engl JMed,2008,358(11):1160-1174.
[109] Cai W, Niu G, Chen X. Multimodality imaging of the HER-kinase axis incancer[J]. Eur J Nucl Med Mol Imaging,2008,35(1):186-208.
[110] Chung C H, Ely K, McGavran L, et al. Increased epidermal growth factorreceptor gene copy number is associated with poor prognosis in head and necksquamous cell carcinomas[J]. J Clin Oncol,2006,24(25):4170-4176.
[111] Bonasera T A, Ortu G, Rozen Y, et al. Potential18F-labeled biomarkers forepidermal growth factor receptor tyrosine kinase[J]. Nucl Med Biol,2001,28(4):359-374.
[112] Pantaleo M, Mishani E, Nanni C, et al. Evaluation of modifiedPEGanilinoquinazoline derivatives as potential agents for EGFR imaging in cancerby small animal PET[J]. Mol maging Biol,2010,12(6):616-625.
[113] Dissoki S, Aviv Y, Laky D, et al. The effect of the [18F]-PEG group on tracerqualification of [4-(phenylamino)-quinazoline-6-yl]-amide moiety-an EGFR putativeirreversible inhibitor[J]. Appl Radiat Isotopes,2007,65(10):1140-1151.
[114] Pal A, Balatoni J, Mukhopadhyay U, et al. Radiosynthesis and initial in vitroevaluation of [18F]FPEG-IPQA-a novel PET radiotracer for imaging EGFRexpression-activity in lung carcinomas[J]. Mol Imaging Biol,2011,13(5):853-861.
[115] Kobus D, Giesen Y, Ullrich R, et al. A Fully Automated Two-Step Synthesis ofAn18F-Labelled Tyrosine Kinase Inhibitor for EGFR Kinase Ativity Imaging inTumors[J]. Appl Radiat Isot,2009,67:1977-1984.
[116] Pisaneschi F, Nguyen Q D, Shamsaei E, et al. Development of A NewEpidermal Growth Factor Receptor Positron Emission Tomography Imaging AgentBased on the3-Cyanoquinoline Core: Synthesis and Biological Evaluation[J].Bioorg Med Chem,2010,18(18):6634-6645.
[117] Denholt C L, Binderup T, Stockhausen M T, et al. Evaluation of4-F-18fluorobenzoyl-FALGEA-NH2as a positron emission tomography tracer forepidermal growth factor receptor mutation variant III imaging in cancer[J]. NuclMed Biol,2011,38(4):509-515.
[118] Li W H, Niu G, Lang L X, et al. PET imaging of EGF receptors using F-18FBEM-EGF in a head and neck squamous cell carcinoma model[J]. Eur J Nucl MedMol Imaging,2012,39(2):300-308.
[119] Miao Z, Ren G, Liu H G, et al. PET of EGFR Expression with an F-18-LabeledAffibody Molecule[J]. J Nucl Med,2012,53(7):1110-1118.
[120] Cai W B, Chen X Y. Multimodality imaging of vascular endothelial growthfactor and vascular endothelial growth factor receptor expression[J]. Frontiers inBioscience,2007,12:4267-4279.
[121] Arico`A, Giantin M, Gelain M E, et al. The role of vascular endothelialgrowth factor and matrix metalloproteinases in canine lymphoma: in vivo and invitro study[J]. BMC Vet Res,2013,9:94.
[122] Ma C Y, Li Y, Zhang X F, et al. Levels of vascular endothelial growth factorand matrix metalloproteinase-9proteins in patients with glioma[J]. Int Med Res,2014,42(1):198-204.
[123] Kniess T, Bergmann R, Kuchar M, et al. Synthesis and radiopharmacologicalinvestigation of3-[4‘-[18F]fluorobenzylidene]-indolin-2-one as possible tyrosinekinase inhibitor[J]. Bioorg Med Chem,2009,17(22):7732-7742.
[124] Ilovich O, Jacobson O, Aviv Y, et al. Formation of fluorine-18labeled diarylureas-labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents forangiogenesis[J]. Bioorg Med Chem,2008,16(8):4242-4251.
[125] Wang H, Gao H K, Guo N, et al. Site-Specific Labeling of scVEGF withFluorine-18for Positron Emission Tomography Imaging[J]. Theranostics,2012,2(6):607-617.
[126] Kiesewetter D O, Kilbourn M R, Landvatter S W, et al. Preparation of fourfluorine-18-labeled estrogens and their selective uptakes in target tissues ofimmature rats[J]. J Nucl Med,1984,25(11):1212-1221.
[127] Oh S J, Chi D Y, Mosdzianowski C, et al. The automatic production of16α-[18F]fluoroestradiol using a conventional [18F]FDG module with a disposablecassette system[J]. Appl Radiat Isot,2007,65(6):676-681.
[128] Mankoff D A, Tewson T J, Eary J F. Analysis of blood clearance and labeledmetabolites for the estrogen receptor tracer [F-18]-16α-fluoroestradiol (FES)[J].Nucl Med Biol,1997,24(4):341-348.
[129] Linden H M, Stekhova S A, Link J M, et al. Quantitative fluoroestradiolpositron emission tomography imaging predicts response to endocrine treatment inbreast cancer[J]. J Clin Oncol,2006,24(18):2793-2799.
[130] Mortimer J E, Dehdashti F, Siegel B A, et al. Metabolic flare: indicator ofhormone responsiveness in advanced breast cancer[J]. J Clin Oncol,2001,19(11):2797-2803.
[131] Dehdashti F, Mortimer J E, Siegel B A, et al. Positron tomographic assessmentof estrogen receptors in breast cancer: comparison with FDG-PET and in vitroreceptor assays[J]. J Nucl Med,1995,36(10):1766-1774.
[132] Peterson L M, Mankoff D A, Lawton T, et al. Quantitative imaging of estrogenreceptor expression in breast cancer with PET and18F-fluoroestradiol[J]. J Nucl Med,2008,49(10):367-374.
[133] van Kruchten M, Glaudemans A W, de Vries E F, et al. PET Imaging ofEstrogen Receptors as a Diagnostic Tool for Breast Cancer Patients Presenting with aClinical Dilemma[J]. J Nucl Med,2012,53(2),182-190.
[134] Fowler A M, Chan S R, Sharp T L, et al. Small-Animal PET of SteroidHormone Receptors Predicts Tumor Response to Endocrine Therapy Using aPreclinical Model of Breast Cancer[J]. J Nucl Med,2012,53(7):1119-1126.
[135] Pomper M G, VanBrocklin H, Thieme A M, et al.11beta-methoxy-,11beta-ethyl-and17alpha-ethynyl-substituted16alphafluoroestradiols:receptor-based imaging agents with enhanced uptake efficiency and selectivity[J]. JMed Chem,1990,33(12):3143-3155.
[136] Jonson S D, Bonasera T A, Dehdashti F, et al. Comparative breast tumorimaging and comparative in vitro metabolism of16-[18F]fluoroestradiol-17and16-[18F]fluoromoxestrol in isolated hepatocytes[J]. Nucl Med Biol,1999,26(1):123-130.
[137] Zhu H, Yang Z, Lin J G, et al. Synthesis and evaluation of fluoroethylcyclofenil analogs: Models for potential estrogen receptor imaging agent[J]. J FluorChem,2012,139:46-52.
[138] Seo J W, Chi D Y, Dence C S, et al. Synthesis and biodistribution offluorine-18-labeled fluorocyclofenils for imaging the estrogen receptor[J]. Nucl MedBiol,2007,34(4):383-390.
[139] Zeelen F J, Vandenbroek A J. Synthesis of16α-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione (Org2058)[J]. Recueil Des Travaux Chimiques DesPays-Bas-Journal of the Royal Netherlands Chemical Society,1985,104(9):239-242.
[140] Dehdashti F, McGuire A H, Vanbrocklin H F, et al. Assessment of21-[18F]fluoro-16α-ethyl-19-norprogesterone as a positron emittingradiopharmaceutical for the detection of progestin receptors in human breastcarcinomas[J]. J Nucl Med,1991,32(8):1532-1537.
[141] Lee J H, Zhou H B, Dence C S, et al. Development of[F-18]fluorinesubstituted Tanaproget as a progesterone receptor imaging agent forpositron emission tomography[J]. Bioconjug Chem,2010,21(6):1096-1104.
[142] Dehdashti F, Laforest R, Gao F, et al. Assessment of Progesterone Receptors inBreast Carcinoma by PET with21-18F-Fluoro-16alpha,17alpha-[(R)-(1’-alphafurylmethylidene)Dioxy]-19-Norpregn-4-Ene-3,20-Dione[J]. J NuclMed,2012,53(3):363-370.
[143] Fowler A M, Chan S R, Sharp T L, et al. Small-Animal PET of SteroidHormone Receptors Predicts Tumor Response to Endocrine Therapy Using aPreclinical Model of Breast Cancer[J]. J Nucl Med,2012,53(7),1119-1126.
[144] Garg S, Doke A, Black K W, et al. In vivo biodistribution of an androgenreceptor avid PET imaging agent7-alpha-fluoro-17alpha-methyl-5-alpha-dihydrotestosterone ([18F]FMDHT) in rats pretreated with cetrorelix, a GnRHantagonist[J]. Eur J Nucl Med Mol Imaging,2008,35(2):379-385.
[145] Liu A J, Katzenellenbogen J A, VanBrocklin H F, et al.20-[18F]fluoromibolerone, a positron-emitting radiotracer for androgen receptors:synthesis and tissue distribution studies[J]. J Nucl Med,1991,32(1):81-88.
[146] Liu A, Dence C S, Welch M J, et al. Fluorine-18-labeled androgens:radiochemical synthesis and tissue distribution studies on six fluorine-substitutedandrogens, potential imaging agents for prostatic cancer[J]. J Nucl Med,1992,33(5):724-734.
[147] Larson S M, Morris M, Gunther I, et al. Tumor localization of16b-18F-fluoro-5a-dyhidrotestosterone versus18F-FDG in patients with progressive,metastatic prostate cancer[J]. J Nucl Med,2004,45(3):366-373.
[148] Dehdashti F, Picus J, Michalski J M, et al. Positron tomographic assessment ofandrogen receptors in prostatic carcinoma[J]. Eur J Nucl Med Mol Imag,2005,32(3):344-350.
[149] Hockel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic,and molecular aspects[J]. J Natl Cancer Inst,2001,93(4):266-276.
[150] Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinicaloutcome[J]. Cancer Metastasis Rev,2007,26(2):225-239.
[151] Hockel M, Schlenger K, Aral B, et al. Association between tumor hypoxia andmalignant progression in advanced cancer of the uterine cervix[J]. Cancer Res,1996,56(19):4509-4515.
[152] Buchler P, Reber H A, Lavey R S, et al. Tumor hypoxia correlates withmetastatic tumor growth of pancreatic cancer in an orthotopic murine model[J]. JSurg Res,2004,120(2):295-303.
[153] Nordsmark M, Bentzen S M, Rudat V, et al. Prognostic value of tumoroxygenation in397head and neck tumors after Primary radiation therapy. Aninternational multi-center study[J]. Radiother Oncol,2005,77(1):18-24.
[154] Krohn K A, Link J M, Mason R P. Molecular imaging of hypoxia[J]. J NuclMed,2008,49(S2):129S-148S.
[155] de Figueiredo B H, Merlin T, de Clermont-Gallerande H, et al. Potential ofF-18-Fluoromisonidazole positron-emission tomography for radiotherapy planningin head and neck squamous cell carcinomas[J]. Strahlenther Onkol,2013,189(12):1015-1019.
[156] Bittner M I, Wiedenmann N, Bucher S, et al. Exploratory geographicalanalysis of hypoxic subvolumes using F-18-MISO-PET imaging in patients withhead and neck cancer in the course of primary chemoradiotherapy[J]. RadiotherOncol,2013,108(3):511-516.
[157] Hatano T, Zhao S J, Zhao Y, et al. Biological characteristics of intratumoralF-18-fluoromisonidazole distribution in a rodent model of glioma[J]. Int J Oncol,2013,42(3):823-830.
[158] Tachibana I, Nishimura Y, Shibata T, et al. A prospective clinical trial of tumorhypoxia imaging with F-18-fluoromisonidazole positron emission tomography andcomputed tomography (F-MISO PET/CT) before and during radiation therapy[J]. JRadiat Res,2013,54(6):1078-1084.
[159] Segard T, Robins P D, Yusoff I F, et al. Detection of Hypoxia WithF-18-Fluoromisonidazole (F-18-FMISO) PET/CT in Suspected or Proven PancreaticCancer[J]. Clin Nucl Med,2013,38(1):1-6.
[160] Piert M, Machulla H J, Picchio M, et al. Hypoxia-specific tumor imaging with18Ffluoroazomycin arabinoside[J]. J Nucl Med,2005,46(1):106-113.
[161] Reischl G, Dorow D S, Cullinane C, et al. Imaging of tumor hypoxia with[124I]IAZA in comparison with [18F] FMISO and [18F]FAZA-first small animal PETresults[J]. J Pharm Pharm Sci,2007,10(2):203-211.
[162] Sorger D, Patt M, Kumar P, et al.(18)F Fluoroazomycinarabinofuranoside((18)FAZA) and (18)F Fluoromisonidazole ([18F]MISO): A comparative study oftheir selective uptake in hypoxic cells and PET imaging in experimental rattumors[J]. Nucl Med Biol,2003,30(3):317-326.
[163] Postema E J, McEwan A J, Riauka T A, et al. Initial results of hypoxia imagingusing1-alpha-D-(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole(18F-FAZA)[J]. Eur J Nucl Med Mol Imaging,2009,36(10):1565-1573.
[164] Bollineni V R, Kerner G, Pruim J, et al. PET Imaging of Tumor Hypoxia UsingF-18-Fluoroazomycin Arabinoside in Stage III-IV Non-Small Cell Lung CancerPatients[J]. J Nucl Med,2013,54(8):1175-1180.
[165] Maier F C, Kneilling M, Reischl G, et al. Significant impact of differentoxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging usingF-18-fluoro-azomycinarabino-furanoside(F-18FAZA)[J]. Radiat Oncol,2011,6:165.
[166] Busk M, Munk O L, Jakobsen S, et al. Assessing hypoxia in animal tumormodels based on pharmacokinetic analysis of dynamic FAZA PET[J]. Acta Oncol,2010,49(7):922-933.
[167] Shi K, Souvatzoglou M, Astner S T, et al. Quantitative assessment of hypoxiakinetic models by a cross-study of dynamic18F-FAZA and15O-H2O in patients withhead and neck tumors[J]. J Nucl Med,2010,51(9):1386-1394.
[168] Verwer E E, van Velden F H P, Bahce I, et al. Pharmacokinetic analysis of F-18FAZA in non-small cell lung cancer patients[J]. Eur J Nucl Med Mol Imaging,2013,40(10):1523-1531.
[169] Dubois L J, Lieuwes N G, Janssen M H M, et al. Preclinical evaluation andvalidation of F-18HX4, a promising hypoxia marker for PET imaging[J]. Proc NatlAcad Sci USA,2011,108(35):14620-14625.
[170] Doss M, Zhang J J, Belanger M J, et al. Biodistribution and radiationdosimetry of the hypoxia marker F-18-HX4in monkeys and humans determined byusing whole-body PET/CT[J]. Nucl Med Commun,2010,31(12):1016-1024.
[171] Chen L M, Zhang Z W, Kolb H C, et al. F-18-HX4hypoxia imaging withPET/CT in head and neck cancer: a comparison with F-18-FMISO[J]. Nucl MedCommun,2012,33(10):1096-1102.
[172] Zegers C M L, van Elmpt W, Wierts R, et al. Hypoxia imaging with F-18HX4PET in NSCLC patients: Defining optimal imaging parameters[J]. Radiother Oncol,2013,109(1):58-64.
[173] Busk M, Jakobsen S, Horsman M R, et al. PET imaging of tumor hypoxiausing F-18-labeled pimonidazole[J]. Acta Oncol,2013,52(7):1300-1307.
[174] Shibahara I, Kumabe T, Kanamori M, et al. Imaging of hypoxic lesions inpatients with gliomas by using positron emission tomography with1-(2-[18F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole, a new18F-labeled2-nitroimidazole analog[J]. J Neurosurg,2010,113(2):358-368.
[175] Beppu T, Terasaki K, Sasaki T, et al. Standardized Uptake Value in HighUptake Area on Positron Emission Tomography with F-18-FRP170as a HypoxicCell Tracer Correlates with Intratumoral Oxygen Pressure in Glioblastoma[J]. MolImaging Biol,2014,16(1):127-135.
[176] Malik N, Lin X, Loffler D, et al. Synthesis of O-2-F-18fluoro-3-(2-nitro-1H-imidazole-1-yl)propyl tyrosine (F-18FNT) as a new class oftracer for imaging hypoxia[J]. J Radioanal Nucl Chem,2012,292(3):1025-1033.
[177] Verma I, Somia N. Gene therapy-promises, problems and prospects[J]. Nature,1997,389(6648):239-342.
[178] Jacobs A, Voges J, Reszka R, et al. Positron-emission tomography ofvector-mediated gene expression in gene therapy for gliomas[J]. Lancet,2001,358(9283):727-729.
[179] Tjuvajev J G, Stockhammer G, Desai R, et al. Imaging the expression oftransfected genes in vivo[J]. Cancer Res,1995,55(24):6126-6132.
[180] Mangner T J, Klecker R W, Anderson L, et al. Synthesis of2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosyl nucleosides ([18F]-FAU),([18F]-FMAU),([18F]-FBAU) and ([18F]-FIAU), as potential PET agents for imagingcellular proliferation[J]. Nucl Med Biol,2003,30(3):215-224.
[181] Cai H C, Li Z B, Conti P S. The improved syntheses of5-substituted2’-F-18fluoro-2’-deoxy-arabinofuranosyluracil derivatives (F-18FAU, F-18FEAU, F-18FFAU, F-18FCAU, F-18FBAU and F-18FIAU) using a multistep one-potstrategy[J]. Nucl Med Biol,2011,38(5):659-666.
[182] Johnson M, Karanikolas B D W, Priceman S J, et al. Titration of VariantHSV1-tk Gene Expression to Determine the Sensitivity of F-18-FHBG PET Imagingin a Prostate Tumor[J]. J Nucl Med,2009,50(5):757-764.
[183] Yaghoubi S, Barrio J R, Dahlbom M, et al. Human pharmacokinetic anddosimetry studies of [18F]FHBG: a reporter probe for imaging herpes simplex virustype-1thymidine kinase reporter gene expression[J]. J Nucl Med,2001,42(8):1225-1234.
[184] Yaghoubi S S, Jensen M C, Satyamurthy N, et al. Noninvasive detection oftherapeutic cytolytic T cells with18F-FHBG in a patient with glioma[J]. Nat ClinPract Oncol,2009,6(1):53-58.
[185] Penuelas I, Mazzolini G, Boan J F, et al. Positron emission tomographyimaging of adeno-viral-mediated transgene expression in liver cancer patients[J].Gastroenterology,2005,128(7):1787-1795.
[186] Yaghoubi S S, Gambhir S S. PET imaging of herpes simplex virus type1thymidine kinase (HSV1-tk) or mutant HSV1-sr39tk re-porter gene expression inmice and humans using [18F]FHBG[J]. Nat Protoc,2007,1(6):3069-3075.
[187] Alauddin M M, Shahinian A, Park R, et al. In vivo evaluation of2’-deoxy-2’-[18F]fluoro-5-iodo-1-beta-Darabinofuranosyluracil ([18F]FIAU) and2’-deoxy-2’-[18F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil ([18F]FEAU) asmarkers for suicide gene expression[J]. Eur J Nucl Med Mol Imaging,2007,34(6):822-829.
[188] Kong X B, Vidal P, Tong W P, et al. Preclinical pharmacology andpharmacokinetics of the anti-hepatitis virus agent2’-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil in mice and rats[J]. Antimicrob Agents Chemother,1992,36(7):1472-1477.
[189] Miyagawa T, Gogiberidze G, Serganova I, et al. Imaging of HSV-tk Reportergene expression: comparison between [18F]FEAU,[18F]FFEAU, and other imagingprobes[J]. J Nucl Med,2008,49(4):637-648.
[190] Chan P C, Wu C Y, Chang W Y, et al. Evaluation of F-18-labeled5-iodocytidine (F-18-FIAC) as a new potential positron emission tomography probefor herpes simplex virus type1thymidine kinase imaging[J]. Nucl Med Biol,2011,38(7):987-995.
[191] Deroose C M, Chitneni S K, Gijsbers R, et al. Preliminary validation ofvaricella zoster virus thymidine kinase as a novel reporter gene for PET[J]. NuclMed Biol,2012,39(8):1266-1274.
[192] Ameisen J C. On the origin, evolution, and nature of programmed cell death: atimeline of four billion years[J]. Cell Death Differ,2002,9(4):367-393.
[193] Fink S L, Cookson B T. Apoptosis, pyroptosis, and necrosis: mechanisticdescription of dead and dying eukaryotic cells[J]. Infect Immun,2005,73(4):1907-1916.
[194] Hanahan D, Weinberg R A. The Hallmarks of Cancer[J]. Cell,2000,100(1):57-70.
[195] Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation[J]. Cell,2011,144(5):646-674.
[196] Kerr J F, Winterford C M, Harmon B V. Apoptosis. Its significance in cancerand cancer therapy[J]. Cancer,1994,73(8):2013-2026.
[197] Evan G I, Vousden K H. Proliferation, cell cycle and apoptosis in cancer[J].Nature,2001,411(6835):342-348.
[198] Kapty J, Murray D, Mercer J. Radiotracers for noninvasive molecular imagingof tumor cell death[J]. Cancer Biother Radiopharm,2010,25(6):615-628.
[199] Blankenberg F G, Strauss H W. Will imaging of apoptosis play a role inclinical care? A tale of mice and men[J]. Apoptosis,2001,6(1-2):117-123.
[200] Tait J F. Imaging of apoptosis[J]. J Nucl Med,2008,49(10):1573-1576.
[201] Murakami Y, Takamatsu H, Taki J, et al.18F-labelled Annexin V: a PET tracerfor apoptosis imaging[J]. Eur J Nucl Med Mol Imaging,2004,31(4):469-474.
[202] Glaser M, Collingridge D R, Aboagye E O, et al. Iodine-124labelledAnnexin-V as a potential radiotracer to study apoptosis using positron emissiontomography[J]. Appl Radiat Isot,2003,58(1):55-62.
[203] Toretsky J, Levenson A, Weinberg I N, et al. Preparation of F-18labeledannexin V: a potential PET radiopharmaceutical for imaging cell death[J]. Nucl MedBiol,2004,31(6):747-752.
[204] Tait J F, CerqueiraM D, Dewhurst T A, et al. Evaluation of Annexin V as aplatelet-directed thrombus targeting agent[J]. Thromb Res,1994,75(5):491-501.
[205] Zhu J C, Wang F, Fang W, et al. F-18-annexin V apoptosis imaging fordetection of myocardium ischemia and reperfusion injury in a rat model[J]. JRadioanal Nucl Chem,2013,298(3):1733-1738.
[206] Grierson J R, Yagle K J, Eary J F, et al. Production of [F-18]fluoroannexin forimaging apoptosis with PET[J]. Bioconjug Chem,2004,15(2):373-379.
[207] Zijlstra S, Gunawan J, Burchert W. Synthesis and evaluation of a18F-labelledrecombinant annexin-V derivative, for identification and quantification of apoptoticcells with PET[J]. Appl Radiat Isot,2003,58(2):201-207.
[208] Hu S, Kiesewetter D O, Zhu L, et al. Longitudinal PET Imaging ofDoxorubicin-Induced Cell Death with F-18-Annexin V[J]. Mol Imaging Biol,2012,14(6):762-770.
[209] Wang M W, Wang F, Zheng Y J, et al. An in vivo molecular imaging probeF-18-Annexin B1for apoptosis detection by PET/CT: preparation and preliminaryevaluation[J]. Apoptosis,2013,18(2):238-247.
[210] Cohen A, Shirvan A, Levin G, et al. From the Gla domain to a novelsmall-molecule detector of apoptosis[J]. Cell Res,2009,19(5):625-637.
[211] Reshef A, Shirvan A, Waterhouse R N, et al. Molecular imaging ofneurovascular cell death in experimental cerebral stroke by PET[J]. J Nucl Med,2008,49(9):1520-1528.
[212] Hoglund J, Shirvan A, Antoni G, et al.18F-ML-10, a PET tracer for apoptosis:first human study[J]. J Nucl Med,2011,52(5):720-725.
[213] Allen A M, Ben-Ami M, Reshef A, et al. Assessment of response of brainmetastases to radiotherapy by PET imaging of apoptosis with F-18-ML-10[J]. Eur JNucl Med Mol Imaging,2012,39(9):1400-1408.
[214] Sobrio F, Medoc M, Martial L,et al. Automated Radiosynthesis of F-18ML-10,a PET Radiotracer Dedicated to Apoptosis Imaging, on a TRACERLab FX-FNModule[J]. Mol Imaging Biol,2013,15(1):12-18.
[215] Grütter MG. Caspases: key players in programmed cell death[J]. Curr OpinStruct Biol,2000,10(6):649-655.
[216] Riedl S J, Shi Y. Molecular mechanisms of caspase regulation duringapoptosis[J]. Nat Rev Mol Cell Biol,2004,5(11):897-907.
[217] Su H L, Chen G, Gangadharmath U, et al. Evaluation of F-18-CP18as a PETImaging Tracer for Apoptosis[J]. Mol Imaging Biol,2013,15(6):739-747.
[218] Xia C F, Chen G, Gangadharmath U, et al. In Vitro and In Vivo Evaluation ofthe Caspase-3Substrate-Based Radiotracer F-18-CP18for PET Imaging ofApoptosis in Tumors[J]. Mol Imaging Biol,2013,15(6):748-757.
[219] Doss M, Kolb H C, Walsh J C, et al. Biodistribution and Radiation Dosimetryof F-18-CP-18, a Potential Apoptosis Imaging Agent, as Determined from PET/CTScans in Healthy Volunteers[J]. J Nucl Med,2013,54(12):2087-2092.
[220] Smith G, Glaser M, Perumal M, et al. Design, Synthesis, and BiologicalCharacterization of A Caspase3/7Selective Isatin Labeled with2-
[18F]fluoroethylazide[J]. J Med Chem,2008,51(24):8057-8067.
[221] Glaser M, Goggi J, Smith G, et al. Improved Radiosynthesis of the ApoptosisMarker [18F]-ICMT11Including Biological Evaluation[J]. Bioorg Med Chem Lett,2011,21(23):6945-6949.
[222] Fortt R, Smith G, Awais R O, et al. Automated GMP Synthesis of F-18ICMT-11for In Vivo Imaging of Caspase-3Activity[J]. Nucl Med Biol,2012,39(7):1000-1005.
[223]Nguyen Q D, Smith G, Glaser M, et al. Positron emission tomography imagingof drug-induced tumor apoptosis with a caspase-3/7specific [18F]-labeled isatinsulfonamide[J]. Proc Nat Acad Sci U.S.A.,2009,106(38):16375-1680.
[224] Challapalli A, Kenny L M, Hallett W A, et al. F-18-ICMT-11, aCaspase-3-Specific PET Tracer for Apoptosis: Biodistribution and RadiationDosimetry[J]. J Nucl Med,2013,54(9):1551-1556.
[225] Forsback S, Eskola O, Haaparanta M, et al. Electrophilic Synthesis of6-[18F]Fluoro-L-DOPA using Post-Target Produced [18F]F2[J]. Radiochim Acta,2008,96:845-848.
[226] Hiller A, Fischer C, Jordanova A, et al. Investigations to the Synthesis of n.c.a.
[18F]FClO3as Electrophilic Fluorinating Agent[J]. Appl Radiat Isot,2008,66:152-157.
[227]陆春雄,王正武,蒋泉福,等.肿瘤增殖显像剂18F-FLT的合成和标记[J].核化学与放射化学,2009,31(1):52-56.
[228] Mu L, Honer M, Becaud J, et al. In Vitro and in Vivo Characterization of Novel18F-Labeled Bombesin Analogues for Targeting GRPR-Positive Tumors[J].Bioconjugate Chem,2010,21:1864-1871.
[229] Qu W C, Zha Z H, Ploessl K, et al. Synthesis of Optically Pure4-Fluoro-glutamines as Potential Metabolic Imaging Agents for Tumors[J]. J AmChem Soc,2011,133:1122-1133.
[230] Kolb H C, Finn M G, Sharpless K B. Click Chemistry: Diverse ChemicalFunction from A Few Good Reactions[J]. Angew Chem Int Ed,2001,40(11):2004-2021.
[231] Rostovtsev V V, Green L G, Fokin V V,et al. A Stepwise HuisgenCycloaddition Process: Copper(I)-Catalyzed Regioselective "Ligation" of Azides andTerminal Alkynes[J]. Angew Chem, Int Ed,2002,41:2596-2599.
[232] Meldal M, Tornoe C W. Cu-Catalyzed Azide-Alkyne Cycloaddition[J]. ChemRev,2008,108:2952-3015.
[233] Grammel M, Luong P, Orth K, et al. A Chemical Reporter for ProteinAMPylation[J]. J Am Chem Soc,2011,133:17103-17105.
[234] Wang Q, Chan T R, Hilgraf R,et al. Bioconjugation by Copper(I)-CatalyzedAzide-Alkyne [3+2] Cycloaddition[J]. J Am Chem Soc,2003,125:3192-3193.
[235] Prescher J A, Bertozzi C R. Chemistry in Living Systems[J]. Nat Chem Biol,2005,1(1):13-21.
[236] Zhan W H, Barnhill H N, Sivakumar K, et al. Synthesis of Hemicyanine Dyesfor ‘Click’ Bioconjugation[J]. Tetrahedron Lett,2005,46:1691-1695.
[237] Srinivasan R, Tan L P, Wu H, et al. High-Throughput Synthesis of AzideLibraries Suitable for Direct “Click” Chemistry and in Situ Screening[J]. Org BiomolChem,2009,7:1821-1828.
[238] Krishnamurthy V R, Wilson J T, Cui W, et al. Chemoselective Immobilizationof Peptides on Abiotic and Cell Surfaces at Controlled Densities[J]. Langmuir,2010,26:7675-7678.
[239] Sanders B C, Friscourt F, Ledin P A, et al. Metal-Free Sequential [3+2]-DipolarCycloadditions using Cyclooctynes and1,3-Dipoles of Different Reactivity[J]. J AmChem Soc,2011,133:949-957.
[240] Sletten E M, Bertozzi C R. From Mechanism to Mouse: A Tale of TwoBioorthogonal Reactions[J]. Accounts Chem Res,2011,44:666-676.
[241] Marik J, Sutcliffe J L. Click for PET: Rapid Preparation of F-18Fluoropeptidesusing Cu-I Catalyzed1,3-dipolar Cycloaddition[J]. Tetrahedron Lett,2006,47:6681-6684.
[242] Glaser M, Arstad E.“Click labeling” with2-[18F]fluoroethylazide for PositronEmission Tomography[J]. Bioconjugate Chem,2007,18:989-993.
[243] Thonon D, Kech C, Paris J, et al. New Strategy for the Preparation of ClickablePeptides and Labeling with1-(Azidomethyl)-4-[18F]-fluorobenzene for PET[J].Bioconjugate Chem,2009,20(4):817-823.
[244] Maschauer S, Einsiedel J, Haubner R, et al. Labeling and Glycosylation ofPeptides using Click Chemistry: A General Approach to18F-Glycopeptides asEffective Imaging Probes for Positron Emission Tomography[J]. Angew Chem IntEd,2010,49:976-979.
[245] Kuboyama T, Nakahara M, Yoshino M, et al. Stoichiometry-Focused18F-Labeling of Alkyne-Substituted Oligodeoxynucleotides usingAzido([18F]fluoromethyl)benzenes by Cu-Catalyzed Huisgen Reaction[J]. BioorgMed Chem,2011,19:249-255.
[246] Mercier F, Paris J, Kaisin G, et al. General Method for Labeling siRNA byClick Chemistry with Fluorine-18for the Purpose of PET Imaging[J]. BioconjugateChem,2011,22(1):108-114.
[247] Kim D H, Choe Y S, Choi J Y, et al.17-4-(2-[18F)Fluoroethyl)-1H-1,2,3-triazol-1-yl-6-thia-heptadecanoic Acid: A Potential Radiotracer for the Evaluationof Myocardial Fatty Acid Metabolism[J]. Bioconjugate Chem,2009,20:1139-1145.
[248] Ramenda T, Kniess T, Bergmann R, et al. Radiolabelling of Proteins withFluorine-18via Click Chemistry[J]. Chem Commun,2009,48:7521-7523.
[249] Devaraj N K, Keliher E J, Thurber G M, et al.18F Labeled Nanoparticles for inVivo PET-CT Imaging[J]. Bioconjugate Chem,2009,20(2):397-401.
[250] Hans J. Wester. Pharmaceutical Radiochemistry (I)[M]. Munich MolecularImaging Handbook Series, Volume1. Fürstenfeldbruck: Scintomics GmbH Lindach,2010,49-59.
[251] Inkster J A H, Guerin B, Ruth T J, et al. Radiosynthesis and Bioconjugation of
[18F]FPy5yne, A Prosthetic Group for the18F Labeling of Bioactive Peptides[J]. JLabel Compd Radiopharm,2008,51:444-452.
[252] Evans H L, Slade R L, Carroll L, et al. Copper-Free Click-A Promising Toolfor Pre-Targeted PET Imaging[J]. Chem Commun,2012,48:991-993.
[253] Iddon L, Leyton J, Indrevoll B, et al. Synthesis and in Vitro Evaluation of
[18F]Fluoroethyl Triazole Labelled Tyr(3) Octreotate Analogues using ClickChemistry[J]. Bioorg Med Chem Lett,2011,21:3122-3127.
[254] Bejot R, Fowler T, Carroll L, et al. Fluorous Synthesis of F-18Radiotracerswith the F-18Fluoride Ion: Nucleophilic Fluorination as the Detagging Process[J].Angew Chem Int Ed,2009,48:586-589.
[255] Bejot R, Carroll L, Bhakoo K, et al. A Fluorous and Click Approach forScreening Potential PET Probes: Evaluation of Potential Hypoxia Biomarkers[J].Bioorg Med Chem,2012,20:324-329.
[256] Glaser M, Solbakken M, Turton D R, et al. Methods for [18F]-Labeling ofRGD Peptides: Comparison of Aminooxy [18F]Fluorobenzaldehyde Condensationwith ‘Click Labeling’ using2-[18F] Fluoroethylazide, and S-alkylation with
[18F]Fluoropropanethiol[J]. Amino Acids,2009,37:717-724.
[257] Ackermann U, O'Keefe G, Lee S T, et al. Synthesis of A [18F]fluoroethyltriazolylthymidine Radiotracer from [18F]2-fluoroethyl Azide and5-Ethynyl-2'-deoxyuridine[J]. J Label Compd Radiopharm,2011,54:260-266.
[258] Schrigten D, Breyholz H J, Wagner S, et al. A New Generation ofRadiofluorinated Pyrimidine-2,4,6-triones as MMP-Targeted Radiotracers forPositron Emission Tomography[J]. J Med Chem,2011,55:223-232.
[259]施玲丽,李剑波,王成,等.整合素αvβ3靶向PET探针18F-c(RGDfK)在Cu(I)催化体系中的点击合成[J].高等学校化学学报,2012,33(2):1486-1489.
[260] Jianbo Li, Lingli Shi, Lina Jia, et al. Radiolabeling of RGD peptide andpreliminary biological evaluation in mice bearing U87MG tumors[J]. Bioorg MedChem,2012,20(12):3850-3855.
[261] McConathy J, Zhou D, Shockley S E, et al. Click Synthesis and BiologicEvaluation of (R)-and (S)-2-Amino-3-1-(2-[18F]Fluoroethyl)-1H-1,2,3Triazol-4-ylPropanoic Acid for Brain Tumor Imaging with Positron Emission Tomography[J].Mol Imaging,2010,9:329-342.
[262]郭飞虎,施玲丽,王妮,等. P-[18F]FSTC的合成和初步动物学评价[J].核化学与放射化学,2010,32(4):236-242.
[263] Kim D H, Choe Y S, Kim B T. Evaluation of4-[18F]Fluoro-1-butyne as ARadiolabeled Synthon for Click Chemistry with Azido Compounds[J]. Appl RadiatIsot,2010,68(2):329-333.
[264]张锦明,张晓军,张宝石,等.自动化“点击合成”正电子标记肽类细胞凋亡显像剂18F-Pen-peptide[J].核技术,2011,34(11):845-850.
[265] Hausner S H, Marik J, Gagnon M K J, et al. In Vivo Positron EmissionTomography (PET) Imaging with An αvβ6Specific Peptide Radiolabeled using18F-“Click” Chemistry: Evaluation and Comparison with the Corresponding4-[18F]Fluorobenzoyl-and2-[18F]Fluoropropionyl-Peptides[J]. J Med Chem,2008,51(19):5901-5904.
[266] Ross T L, Honer M, Lam P Y H, et al. Fluorine-18Click Radiosynthesis andPreclinical Evaluation of A New18F-Labeled Folic Acid Derivative[J]. BioconjugateChem,2008,19(12):2462-2470.
[267] Kim D H, Choe Y S, Jung K H,et al. A18F-Labeled Glucose Analog: Synthesisusing A Click Labeling Method and in Vitro Evaluation[J]. Arch Pharm Res,2008,31(5):587-593.
[268] Sirion U, Kim H J, Lee J H, et al. An Efficient F-18Labeling Method for PETStudy: Huisgen1,3-Dipolar Cycloaddition of Bioactive Substances andF-18-Labeled Compounds[J]. Tetrahedron Lett,2007,48(23):3953-3957.
[269] Li Z B, Wu Z, Chen K, et al. Click Chemistry for18F-Labeling of RGDPeptides and MicroPET Imaging of Tumor Integrin αvβ3Expression[J]. BioconjugateChem,2007,18(6):1987-1994.
[270] Michel K, Büther K, Law M P, et al. Development and Evaluation ofEndothelin-A Receptor (Radio)Ligands for Positron Emission Tomography[J]. J MedChem,2011,54(4):939-948.
[271] Gill H S, Marik J. Preparation of18F-Labeled Peptides using theCopper(I)-Catalyzed Azide-Alkyne1,3-Dipolar Cycloaddition[J]. Nat Protoc,2011,6(11):1718-1725.
[272] Ramenda T, Bergmann R, Wuest F. Synthesis of18F-LabeledNeurotensin(8-13) via Copper-Mediated1,3-Dipolar [3+2]CycloadditionReaction[J]. Lett Drug Des Discov,2007,4:279-285.
[273] Lemaire C E, Aerts J J, Voccia S, et al. Fast Production of Highly ReactiveNo-Carrier-Added F-18Fluoride for the Labeling of Radiopharmaceuticals[J].Angew Chem, Int Ed,2010,49:3161-3164.
[274] Maschauer S, Prante O. A Series of2-O-trifluoromethylsulfonyl-D-mannopyranosides as Precursors for Concomitant [18F]-Labeling and Glycosylationby Click Chemistry[J]. Carbohydr Res,2009,344:753-761.
[275] Boutureira O, D'Hooge F, Fernandez-Gonzalez M, et al. Fluoroglycoproteins:Ready Chemical Site-Selective Incorporation of Fluorosugars into Proteins[J]. ChemCommun,2010,46:8142-8144.
[276] Fischer C R, Müller C, Reber J, et al.[18F]Fluoro-Deoxy-Glucose Folate: ANovel PET Radiotracer with Improved in Vivo Properties for Folate ReceptorTargeting[J]. Bioconjugate Chem,2012,23:805-813.
[277] Inkster J A H, Adam M J, Storr T, et al. Labeling of An AntisenseOligonucleotide with F-18FPy5yne[J]. Nucleosides Nucleotides Nucleic Acids,2009,28:1131-1143.
[278] Kuhnast B, Hinnen F, Tavitian B,et al.[18F]FPyKYNE, aFluoropyridine-Based Alkyne Reagent Designed for the Fluorine-18Labelling ofMacromolecules using Click Chemistry[J]. J Label Compd Radiopharm,2008,51,336-342.
[279] Valdivia A C, Estrada M, Hadizad T, et al. A Fast, Simple, and ReproducibleAutomated Synthesis of [18F]FPyKYNE-c(RGDyK) for αvβ3Receptor PositronEmission Tomography Imaging[J]. J Label Compd Radiopharm,2012,55:57-60.
[280] Gaetke L M, Chow C K. Copper Toxicity, Oxidative Stress, and AntioxidantNutrients[J]. Toxicology,2003,189:147-163.
[281] Brewer G J. Copper Toxicity in the General Population[J]. Clin Neurophysiol,2010,12:459-460.
[282] Campbell-Verduyn L S, Mirfeizi L, Schoonen A K, et al. Strain-PromotedCopper-Free “Click” Chemistry for18F Radiolabeling of Bombesin[J]. Angew ChemInt Ed,2011,50:11117-11120.
[283] Bouvet V, Wuest M, Wuest F. Copper-Free Click Chemistry with theShort-Lived Positron Emitter Fluorine-18[J]. Org Biomol Chem,2011,9:7393-7399.
[284] Carpenter R D, Hausner S H, Sutcliffe J L. Copper-Free Click for PET: Rapid1,3-Dipolar Cycloadditions with A Fluorine-18Cyclooctyne[J]. ACS Med ChemLett,2011,2:885-889.
[285] Arumugam S, Chin J, Schirrmacher R, et al.[18F] Azadibenzocyclooctyne([18F]ADIBO): A Biocompatible Radioactive Labeling Synthon for Peptides usingCatalyst Free [3+2] Cycloaddition[J]. Bioorg Med Chem Lett,2011,21:6987-6991.
[286] Zhang L, Chen X G, Xue P, et al. Ruthenium-Catalyzed Cycloaddition ofAlkynes and Organic Azides[J]. J Am Chem Soc,2005,127:15998-15999.
[287] Majireck M M, Weinreb S M. A Study of the Scope and Regioselectivity of theRuthenium-Catalyzed [3+2]-Cycloaddition of Azides with Internal Alkynes[J]. J OrgChem,2006,71:8680-8683.
[288] Boren B C, Narayan S, Rasmussen L K, et al. Ruthenium-CatalyzedAzide-Alkyne Cycloaddition: Scope and Mechanism[J]. J Am Chem Soc,2008,130:8923-8930.
[289] Liu P N, Li J, Su F H, et al. Selective Formation of1,4-Disubstituted Triazolesfrom Ruthenium-Catalyzed Cycloaddition of Terminal Alkynes and Organic Azides:Scope and Reaction Mechanism[J]. Organometallics,2012,31:4904-4915.
[290] Dowling R H, Mack E, Small D M. Effects of controlled interruption of theenterohepatic circulation of bile salts by biliary diversion and by ileal resection onbile salt secretion, synthesis, and pool size in the rhesus monkey[J]. J Clin Invest,1970,49(2):232-242.
[291] Hofmann A F, Hagey L R. Bile acids: Chemistry, pathochemistry, biology,pathobiology, and therapeutics[J]. Cell Mol Life Sci,2008,65(16):2461-2483.
[292] Rao Y P, Vlahcevic Z R, Stravitz R T, et al. Down-regulation of the rat hepaticsterol27-hydroxylase gene by bile acids in transfected primary hepatocytes: possiblerole of hepatic nuclear factor1alpha[J]. J Steroid Biochem Mol Biol,1999,70(1-3):1-14.
[293] Inagaki T, Choi M, Moschetta A, et al. Fibroblast growth factor15functions asan enterohepatic signal to regulate bile acid homeostasis[J]. Cell Metab,2005,2(4):217-225.
[294] Yu C D, Wang F, Jin C L, et al. Independent repression of bile acid synthesisand activation of c-Jun N-terminal kinase (JNK) by activated hepatocyte fibroblastgrowth factor receptor4(FGFR4) and bile acids[J]. J Biol Chem,2005,280(18):17707-17714.
[295] Chawla A, Repa J J, Evans R M, et al. Nuclear receptors and lipid physiology:Opening the X-files. Science,2001,294(5548):1866-1870.
[296] Maruyama T, Miyamoto Y, Nakamura T, et al. Identification of membrane-typereceptor for bile acids (M-BAR)[J]. Biochem Biophys Res Commun,2002,298(5):714-719.
[297] Kawamata Y, Fujii R, Hosoya M, et al. A G protein-coupled receptorresponsive to bile acids[J]. J Biol Chem,2003,278(11):9435-9440.
[298] Gioiello A, Macchiarulo A, Carotti A, et al. Extending SAR of bile acids asFXR ligands: Discovery of23-N-(carbocinnamyloxy)-3alpha,7alpha-dihydroxy-6alpha-ethyl-24-nor-5beta-cholan-23-amine[J]. Bioorg Med Chem,2011,19(8):2650-2658.
[299] Fiorucci S, Mencarelli A, Distrutti E, et al. Targeting Farnesoid-X-Receptor:From Medicinal Chemistry to Disease Treatment[J]. Curr Med Chem,2010,17(2):139-159.
[300] Zhang Y Q, Kast-Woelbern H R, Edwards P A. Natural structural variants ofthe nuclear receptor farnesoid X receptor affect transcriptional activation[J]. J BiolChem,2003,278(1):104-110.
[301] Pircher P C, Kitto J L, Petrowski M L, et al. Farnesoid X receptor regulatesbile acid-amino acid conjugation[J]. J Biol Chem,2003,278(30):27703-27711.
[302] Huang W D, Ma K, Zhang J, et al. Nuclear receptor-dependent bile acidsignaling is required for normal liver regeneration[J]. Science,2006,312(5771):233-236.
[303] Kim I, Morimura K, Shah Y, et al. Spontaneous hepatocarcinogenesis infarnesoid X receptor-null mice[J]. Carcinogenesis,2007,28(5):940-946.
[304] Yang F, Huang X F, Yi T S, et al. Spontaneous development of liver tumors inthe absence of the bile acid receptor farnesoid X receptor[J]. Cancer Res,2007,67(3):863-867.
[305] Kim I, Ahn S H, Inagaki T, et al. Differential regulation of bile acidhomeostasis by the farnesoid X receptor in liver and intestine[J]. J Lipid Res,2007,48(12):2664-2672.
[306] Maran R R M, Thomas A, Roth M, et al. Farnesoid X Receptor Deficiency inMice Leads to Increased Intestinal Epithelial Cell Proliferation and TumorDevelopment[J]. J Pharmacol Exp Ther,2009,328(2):469-477.
[307] Moschetta A, Bookout A L, Mangelsdorf D J. Prevention of cholesterolgallstone disease by FXR agonists in a mouse model[J]. Nat Med,2004,10(12):1352-1358.
[308] Stedman C, Liddle C, Coulter S, et al. Benefit of farnesoid X receptorinhibition in obstructive cholestasis[J]. Proc Natl Acad Sci U. S. A.,2006,103(30):11323-11328.
[309] Guo G L, Santamarina-Fojo S, Akiyama T E, et al. Effects of FXR infoam-cell formation and atherosclerosis development[J]. Biochim Biophys Acta MolCell Biol Lipids,2006,1761(12):1401-1409.
[310] Modica S, Petruzzelli M, Bellafante E, et al. Selective Activation of NuclearBile Acid Receptor FXR in the Intestine Protects Mice Against Cholestasis[J].Gastroenterology,2012,142(2):355-365.
[311] Zhang L S, Wang Y D, Chen W D, et al. Promotion of LiverRegeneration/Repair by Farnesoid X Receptor in Both Liver and Intestine in Mice[J].Hepatology,2012,56(6):2336-2343.]312] Chen F, Ananthanarayanan M, Emre S, et al. Progressive familial intrahepaticcholestasis, type1, is associated with decreased farnesoid X receptor activity[J].Gastroenterology,2004,126(3):756-764.
[313] De Gottardi A, Touri F, Maurer CA, et al. The bile acid nuclear receptor FXRand the bile acid binding protein IBABP are differently expressed in colon cancer[J].Dig Dis Sci,2004,49(6):982-989.
[314] Takahara Y, Takahashi M, Zhang Q W, et al. Serial changes in expression offunctionally clustered genes in progression of liver fibrosis in hepatitis C patients[J].World J Gastroenterol,2008,14(13):2010-2022.
[315] Fickert P, Fuchsbichler A, Moustafa T, et al. Farnesoid X Receptor CriticallyDetermines the Fibrotic Response in Mice but Is Expressed to a Low Extent inHuman Hepatic Stellate Cells and Periductal Myofibroblasts[J]. Am J Pathol,2009,175(6):2392-2405.
[316] Wolfe A, Thomas A, Edwards G, et al. Increased Activation of theWnt/beta-Catenin Pathway in Spontaneous Hepatocellular Carcinoma Observed inFarnesoid X Receptor Knockout Mice[J]. J Pharmacol Exp Ther,2011,338(1):12-21.
[317] Lax S, Schauer G, Prein K, et al. Expression of the nuclear bile acidreceptor/farnesoid X receptor is reduced in human colon carcinoma compared tononneoplastic mucosa independent from site and may be associated with adverseprognosis[J]. Int J Cancer,2012,130(10):2232-2239.
[318] Meng Z P, Wang X Q, Gan Y C, et al. Deletion of IFN gamma enhanceshepatocarcinogenesis in FXR knockout mice[J]. J Hepatol,2012,57(5):1004-1012.
[319] Elsharkawy A M, Mann D A. Nuclear factor-kappa B and the hepaticinflammation-fibrosis-cancer axis[J]. Hepatology,2007,46(2):590-597.
[320] Liu N A, Meng Z P, Lou G Y, et al. Hepatocarcinogenesis in FXR-/-MiceMimics Human HCC Progression That Operates through HNF1alpha Regulation ofFXR Expression[J]. Mol Endocrinol,2012,26(5):775-785.
[321] Vavassori P, Mencarelli A, Renga B, Distrutti E, Fiorucci S. The Bile AcidReceptor FXR Is a Modulator of Intestinal Innate Immunity[J]. J Immunol,2009,183(10):6251-6261.
[322] Fiorucci S, Cipriani S, Mencarelli A, et al. Counter-Regulatory Role of BileAcid Activated Receptors in Immunity and Inflammation[J]. Curr Mol Med,2010,10(6):579-595.
[323] Frisch K, Jakobsen S, Sorensen M, et al. N-Methyl-C-11Cholylsarcosine, aNovel Bile Acid Tracer for PET/CT of Hepatic Excretory Function: Radiosynthesisand Proof-of-Concept Studies in Pigs[J]. J Nucl Med,2012,53(5):772-778.
[324] Anelli PL, Lattuada L, Lorusso V, et al. Conjugates of gadolinium complexesto bile acids as hepatocyte-directed contrast agents for magnetic resonanceImaging[J]. J Med Chem,2004,47(14):3629-3641.
[325] Makishima M, Okamoto AY, Repa JJ, et al. Identification of a nuclear receptorfor bile acids[J]. Science,1999,284(5418):1362-1365.
[326] Wang H B, Chen J, Hollister K, et al. Endogenous bile acids are ligands for thenuclear receptor FXR BAR[J]. Mol Cell,1999,3(5):543-553.
[327] Parks D J, Blanchard S G, Bledsoe R K, et al. Bile acids: Natural ligands for anorphan nuclear receptor. Science,1999,284(5418):1365-1368.
[328] Pellicciari R, Gioiello A, Costantino G, et al. Back door modulation of thefarnesoid X receptor: Design, synthesis, and biological evaluation of a series of sidechain modified chenodeoxycholic acid derivatives[J]. J Med Chem,2006,49(14):4208-4215.
[329] Russell D W. The enzymes, regulation, and genetics of bile acid synthesis[J].Annu Rev Biochem,2003,72:137-174.
[330] Tiwari A, Maiti P. TGR5: an emerging bile acid G-protein-coupled receptortarget for the potential treatment of metabolic disorders[J]. Drug Discov Today,2009,14(9-10):523-530.
[331] Pols T W H, Noriega L G, Nomura M, et al. The bile acid membrane receptorTGR5as an emerging target in metabolism and inflammation[J]. J Hepatol,2011,54(6):1263-1272.
[332] Katsuma S, Hirasawa A, Tsujimoto G. Bile acids promote glucagon-likepeptide-1secretion through TGR5in a murine enteroendocrine cell line STC-1[J].Biochem Biophys Res Commun,2005,329(1):386-390.
[333] Watanabe M, Houten S M, Mataki C, et al. Bile acids induce energyexpenditure by promoting intracellular thyroid hormone activation[J]. Nature,2006,439(7075):484-489.
[334] Cipriani S, Mencarelli A, Chini M G, et al. The Bile Acid Receptor GPBAR-1(TGR5) Modulates Integrity of Intestinal Barrier and Immune Response toExperimental Colitis[J]. Plos One,2011,6(10):1-11.
[335] Yang J I, Yoon J H, Myung S J, et al. Bile acid-induced TGR5-dependentc-Jun-N terminal kinase activation leads to enhanced caspase8activation inhepatocytes[J]. Biochem Biophys Res Commun,2007,361(1):156-161.
[336] Yasuda H, Hirata S, Inoue K, et al. Involvement of membrane-type bile acidreceptor M-BAR/TGR5in bile acid-induced activation of epidermal growth factorreceptor and mitogen-activated protein kinases in gastric carcinoma cells[J].Biochem Biophys Res Commun2007,354(1):154-159.
[337] Cao W B, Tian W, Hong J, et al. Expression of bile acid receptor TGR5ingastric adenocarcinoma[J]. Am J Physiol.-Gastroint Liver Physiol,2013,304(4):G322-G327.
[338] Keitel V, Reinehr R, Reich M, et al. THE MEMBRANE-BOUND BILE ACIDRECEPTOR TGR5(GPBAR-1) IS HIGHLY EXPRESSED IN INTRAHEPATICCHOLANGIOCARCINOMA [C]. Hepatology,2011,54:769A.
[339] Hong J, Behar J, Wands J, et al. Role of a novel bile acid receptor TGR5in thedevelopment of oesophageal adenocarcinoma[J]. Gut,2010,59(2):170-180.
[340]郑鹏.胆汁酸受体TGR5和FXR在结直肠癌中的表达及临床意义[D].兰州：兰州大学，2012.
[341] Tiwari A, Maiti P. TGR5: an emerging bile acid G-protein-coupled receptortarget for the potential treatment of metabolic disorders[J]. Drug Discov Today,2009,14(9-10):523-530.
[342] Uppal J K, Varshney R, Hazari P P, et al. Biological evaluation of avidin-basedtumor pretargeting with DOTA-Triazole-Biotin constructed via versatile Cu(I)catalyzed click chemistry[J]. J Drug Target,2011,19(6):418-426.
[343] Lewis M R, Wang M, Axworthy D B, et al. In vivo evaluation of pretargetedCu-64for tumor imaging and therapy [J]. J Nucl Med,2003,44(8):1284-1292.
[344] Marysael T, Bauwens M, Ni Y C, et al. Pretargeting of necrotic tumors withbiotinylated hypericin using I-123-labeled avidin: evaluation of a two-stepstrategy[J]. Invest New Drugs,2012,30(6):2132-2140.
[345] Boerman O C, Kranenborg M, Oosterwijk E, et al. Pretargeting of renal cellcarcinoma: Improved tumor targeting with a bivalent chelate[J]. Cancer Res,1999,59(17):4400-4405.
[346] Goldenberg D M, Sharkey R M, Paganelli G, et al. Antibody pretargetingadvances cancer radioimmunodetection and radioimmunotherapy[J]. J Clin Oncol,2006,24(5):823-834.
[347] Knox S J, Goris M L, Tempero M, et al. Phase II trial ofyttrium-90-DOTA-biotin pretargeted by NR-LU-10antibody/streptavidin in patientswith metastatic colon cancer[J]. Clin Cancer Res,2000,6(2):406-414.
[348] Sakahara H, Saga T. Avidin-biotin system for delivery of diagnostic agents[J].Adv Drug Deliv Rev,1999,37(1-3):89-101.
[349] Mawad R, Gooley T, Rajendran J G, et al. Pretargeted RadioimmunotherapyUsing an Anti-CD45Antibody-Streptavidin Conjugate and RadiolabeledDOTA-Biotin in Patients with High-Risk Acute Leukemia or MyelodysplasticSyndrome Undergoing Allogeneic Hematopoietic Cell Transplantation[J]. BiolBlood Marrow Transplant,2013,19(2): S123-S124.
[350] Subbiah K, Hamlin D K, Pagel J M, et al. Comparison of immunoscintigraphy,efficacy, and toxicity of conventional and pretargeted radioimmunotherapy inCD20-expressing human lymphoma xenografts[J]. J Nucl Med,2003,44(3):437-445.
[351]郑文莉,李贵平.亲和素-生物素系统预定位放免治疗白血病的研究[J].放射免疫学杂志,2013,26(4):428-432.
[352] Lesch H P, Kaikkonen M U, Pikkarainen J T, et al. Avidin-biotin technology intargeted therapy[J]. Expert Opin Drug Deliv,2010,7(5):551-564.
[353] Sung C, Vanosdol W W, PHARMACOKINETIC COMPARISON OF DIRECTANTIBODY TARGETING WITH PRETARGETING PROTOCOLS BASED ONSTREPTAVIDIN-BIOTIN BINDING[J]. J Nucl Med,1995,36(5):867-876.
[354] Claesener M, Breyholz H J, Hermann S, et al. Efficient synthesis of afluorine-18labeled biotin derivative[J]. Nucl Med Biol,2012,39(8):1189-1194.
[355] Simpson M, Trembleau L, Cheyne R W, et al. One pot production of18F-biotinby conjugation with18F-FDG for pre-targeted imaging: synthesis and radiolabellingof a PEGylated precursor[J]. Appl Radiat Isot,2011,69:418-422.
[356] Smith T A D, Simpson M, Cheyne R, et al.18F-PEG-biotin: precursor(boroaryl-PEG-biotin) synthesis,18F-labelling and an in-vitro assessment of itsbinding with NeutravidinTM–trastuzumab pre-treated cells[J]. Appl Radiat Isot,2011,69:1395-1400.
[357] Blom E, Itsenko O, Langstrom B. Synthesis of F-18-labelled biotinanalogues[J]. J Label Compd Radiopharm,2011,54(9-10):681-683.
[358] Ting R, Harwig C, auf dem Keller U, et al. Toward [18F]-labeledaryltrifluoroborate radiotracers: in vivo positron emission tomography imaging ofstable aryltrifluoroborate clearance in mice[J]. J Am Chem Soc,2008,130:12045-12055.
[359] Ting R, Adam M J, Ruth T J, et al. Arylfluoroborates and alkylfluorosilicatesas potential PET imaging agents: high-yielding aqueous biomolecular18F-labeling[J].J Am Chem Soc,2005,127:13094-13095.
[360] Shoup T M, Fischman A J, Jaywook S, et al. Synthesis of Fluorine-18-LabeledBiotin Derivatives: Biodistribution and Infection Localization[J]. J Nucl Med,1994,35(10):1685-1690.
[361] Shankar V, Lilja S, Brigitte V. A broad overview of positron emissiontomography radiopharmaceuticals and clinical applications: What is new?[J]. SeminNucl Med,2011,41:246-264.
[362] Pimlott S L, Sutherland A. Molecular tracers for the PET and SPECT imagingof disease[J]. Chem Soc Rev,2011,40(1):149-162.
[363] Josephs D, Spicer J, O’Doherty M. Molecular imaging in clinical trials[J].Target Oncol,2009,4(3):151-168.
[364] Fletcher J W, Djulbegovic B, Soares H P, et al. Recommendations on the Useof18F-FDG PET in Oncology[J]. J Nucl Med,2008,49:480-508.
[365] Hans J W. Munich Molecular Imaging Handbook Series: PharmaceuticalRadiochemistry (I)[M]. Germany, SCINTOMICS GmbH,2010.
[366] Inkster J, Lin K S, Ait-Mohand S, et al.2-Fluoropyridine prostheticcompounds for the F-18labeling of bombesin analogues[J]. Bioorg Med Chem Lett,2013,23(13),3920-3926.