Re/99Tcm(CO)3+-二苯基二氮烯类化合物Aβ显像剂的制备以及生物评价

doi:10.7538/tws.2013.26.02.0065

摘要/Abstract

摘要：

合成了二苯基二氮烯类衍生物（(E)-2-(4-((4-(二甲基氨基)苯基)二氮烯基)苯基氨基)乙酸）为配体L，采用[⁹⁹Tc^m(CO)₃(H₂O)₃]⁺核心进行放射性标记，得到放化纯度大于95%的标记化合物⁹⁹Tc^m(CO)₃⁺-L，同时合成了相应的Re(CO)₃⁺-L。放射性自显影结果表明，⁹⁹Tc^m(CO)₃⁺-L与AD小鼠（TgC57，APP，PS112个月）大脑切片中的Aβ斑块特异性结合，并且结合位点与Re(CO)₃⁺-L荧光染色的位点相同。在正常小鼠体内的生物分布结果表明，⁹⁹Tc^m(CO)₃⁺-L具有相对较低的脑摄取，5 min为（0.52±0.11）%ID/g，120 min为（0.28±0.04）%ID/g,可知其脑清除较慢。同时进行Re(CO)₃⁺-L化合物的紫外吸收以及荧光光谱分析，确定其在室温下为低电子激发态。以上结果表明，⁹⁹Tc^m(CO)₃⁺-L有望作为Aβ斑块SPECT显像剂，值得进一步研究。

关键词: Re/⁹⁹Tc^m(CO)₃⁺-L, Aβ斑块, 放射性自显影, 荧光染色

Abstract:

To develop the non-invasiveand diagnostic agents for Alzheimer’s disease (AD), ⁹⁹Tc^m(CO)₃⁺-L(L: (E)-2-(4-((4-(dimethylamino)phenyl)diazenyl)phenylamino)acetic acid, adiphenyldiazene derivative) was prepared，radiochemical purity was above 95%. Initialautoradiography results suggested that ⁹⁹Tc^m(CO)₃⁺-Lshowed selective binding to the Aβ plaque-like structures in the brain section from theAD transgenic mice (Tg C57, APP, PS1 12-month-old), further, ⁹⁹Tc^m(CO)₃⁺-Lshowed the same binding sites with fluorescence stained by Re(CO)₃⁺-L.Biodistribution of ⁹⁹Tc^m(CO)₃⁺-L innormal mice demonstrated low uptake in brain (5 min: （0.52 ±0.11)% ID/g）whilst slow clearance from the brain tissues at 120 min post-injection (0.28 ± 0.04)%ID/g. The corresponding Re analogue was alsosynthesized, and the nature of its lowest electronically excited state wasdetermined by studies of the UV-vis absorption and fluorescence emissionproperties at room temperature. In addition, the fluorescent staining of the Re-complexwas performed in comparison to Thioflavin-T and autoradiography results of ⁹⁹Tc^m(CO)₃⁺-L.In conclusion, these results are encouraging for further exploration of ⁹⁹Tc^m(CO)₃⁺-Las a SPECT imaging agent for Aβplaques in the AD brain.

Key words: Re/⁹⁹Tc^m(CO)₃⁺-L, A&beta, plaques, autoradiography, fluorescent staining

杨洋;崔孟超;汤睿昆;吴瑞;朱霖;张华北. Re/⁹⁹Tc^m(CO)₃+-二苯基二氮烯类化合物Aβ显像剂的制备以及生物评价[J]. 同位素, 2013, 26(2): 65-72.

YANG Yang;CUI Meng-chao;TANG Rui-kun;WU Rui;ZHU Lin;ZHANG Hua-bei. Preparation and BiologicalEvaluation of Re/⁹⁹Tc^m(CO)₃⁺-diphenyldiazeneDerivative as Candidates for Imaging Aβ Plaques in the Brain[J]. Journal of Isotopes, 2013, 26(2): 65-72.

参考文献

[1]Selkoe D，Alzheimer J.disease: mechanisticunderstanding predicts novel therapies [J]. Ann Intern Med, 2004, 140 (8): 627-638.

[2]Mathis CA, Wang Y, Klunk WE. Imaging beta-amyloidplaques and neurofibrillary tangles in the aging human brain [J]. Curr PharmDes, 2004, 10 (13): 1469-1492.

[3]Kung MP, Hou C, Zhuang ZP， etal. Characterization of IMPY as a potential imaging agent for beta-amyloidplaques in double transgenic PSAPP mice [J]. Eur J Nucl Med Mol Imaging, 2004,31 (8): 1136-1145.

[4]Zhang W， Oya S, Kung M P, et al. F-18 Stilbenes as PETimaging agents for detecting beta-amyloid plaques in the brain [J]. J Med Chem,2005, 48 (19): 5980-5988.

[5]Zhang W， Oya S, Kung M P， et al. F-18 Polyethyleneglycol stilbenes as PET imaging agentstargeting Abeta aggregates in the brain [J]. Nucl Med Biol, 2005, 32 (8): 799-809.

[6]Agdeppa ED,Kepe V, Liu J, et al. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidenederivatives as positron emission tomography imaging probes for beta-amyloidplaques in Alzheimer's disease [J]. J Neurosci, 2001, 21 (24): RC189.

[7]Verhoeff NP,Wilson AA, Takeshita S， et al. In-vivo imaging of Alzheimer disease beta-amyloidwith [¹¹C]SB-13PET [J]. Am J Geriatr Psychiatry, 2004, 12 (6): 584-595.

[8]Klunk WE, Engler H, Nordberg A, et al. Imagingbrain amyloid in Alzheimer's disease with Pittsburgh Compound-B [J]. AnnNeurol, 2004, 55 (3): 306-319.

[9]Kung MP, Hou C, Zhuang ZP，etal. Characterization of IMPY as a potential imaging agent for beta-amyloidplaques in double transgenic PSAPP mice [J]. Eur J Nucl Med Mol Imaging， 2004, 31 (8): 1136-1145.

[10]Zhuang ZP, Kung MP, Hou C, et al. Biphenylslabeled with technetium 99mfor imaging beta-amyloid plaques in the brain [J]. Nucl Med Biol, 2005, 32 (2):171-184.

[11]Chen X, Yu P, Zhang L, et al. Synthesis andbiological evaluation of ^99mTc, Re-monoamine-monoamide conjugated to2-(4-aminophenyl)benzothiazole as potential probes for beta-amyloid plaques inthe brain [J]. Bioorg Med Chem Lett, 2008, 18 (4): 1442-1445.

[12]Han H, Cho C, Lansbury Jr PT. Technetium Complexesfor the Quantitation of Brain Amyloid [J]. J Am Chem Soc, 1996, 118 (18): 4506-4507.

[13]Jurisson SS, Lydon JD. Potential technetium smallmolecule radiopharmaceuticals [J]. Chem Rev, 1999, 99 (2):2205-2218.

[14]Deutsch E, Libson K, Vanderheyden JL, et al. Thechemistry of rhenium and technetium as related to the use of isotopes of theseelements in therapeutic and diagnostic nuclear medicine [J]. Nucl Med Biol,1986, 13 (4): 465-477.

[15]Dilworth J, Parrot S. The biomedical chemistry oftechnitium and rhenium [J]. Chem Soc Rev, 1998, 27: 43-55.

[16]Alberto R, Schibli R, Schubiger AP, et al. FirstApplication of fac-[^99mTc(OH₂)₃(CO)₃]⁺in Bioorganometallic Chemistry: Design, Structure, and in Vitro Affinity of a 5-HT1A Receptor Ligand Labeled with ^99mTc[J]. Am Chem Soc, 1999, 121 (25):6076-6077.

[17]Li Z, Cui M, Dai J,et al. Novel CyclopentadienylTricarbonyl Complexes of ^99mTc Mimicking Chalcone as PotentialSingle-Photon Emission Computed Tomography Imaging Probes for β-AmyloidPlaques in Brain [J]. J Med Chem， 2013, 56(2): 471-482.

[18]Biancalana M, Koide S.Molecular mechanism of Thioflavin-T binding to amyloid fibrils [J]. BiochimBiophys Acta, 2010, 1 804(7): 1405-1412.

Re/⁹⁹Tc^m(CO)₃+-二苯基二氮烯类化合物Aβ显像剂的制备以及生物评价

Preparation and BiologicalEvaluation of Re/⁹⁹Tc^m(CO)₃⁺-diphenyldiazeneDerivative as Candidates for Imaging Aβ Plaques in the Brain

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