新型 N-氟吡啶基托烷衍生物的合成与评价作为多巴胺转运体的潜在 PET 成像剂。
Synthesis and evaluation of novel N-fluoropyridyl derivatives of tropane as potential PET imaging agents for the dopamine transporter.
机构信息
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, Beijing 100875, PR China.
出版信息
Bioorg Med Chem Lett. 2011 May 15;21(10):2962-5. doi: 10.1016/j.bmcl.2011.03.051. Epub 2011 Mar 21.
Abstract
A series of novel N-fluoropyridyl-containing tropane derivatives were synthesized and their binding affinities for the dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine (NET) were determined via competitive radioligand binding assays. Among these derivatives, compound 6d showed the highest binding affinity to DAT (K(i)=4.1 nM), and selectivity for DAT over SERT (5-fold) and NET (16-fold). Compound 6d was radiolabeled with Fluorine-18 in two steps. Regional brain distribution and ex vivo autoradiography studies of [(18)F]6d demonstrated that the ligand was selectively localized in the striatum region, where DAT binding sites are highly expressed. [(18)F]6d may be useful as a potential radioligand for imaging DATs with PET.
摘要
一系列新型含 N-氟吡啶的托烷衍生物被合成出来，并通过竞争性放射性配体结合实验测定了它们对多巴胺转运体（DAT）、5-羟色胺转运体（SERT）和去甲肾上腺素（NET）的结合亲和力。在这些衍生物中，化合物 6d 对 DAT 的亲和力最高（Ki=4.1 nM），对 DAT 的选择性是 SERT 的 5 倍，NET 的 16 倍。化合物 6d 经两步法用氟-18 进行放射性标记。[(18)F]6d 的脑区分布和离体放射性自显影研究表明，该配体选择性地定位于纹状体区域，该区域 DAT 结合位点高表达。[(18)F]6d 可能是一种用于 PET 成像 DAT 的潜在放射性配体。
相似文献
1
Synthesis and evaluation of novel N-fluoropyridyl derivatives of tropane as potential PET imaging agents for the dopamine transporter.新型 N-氟吡啶基托烷衍生物的合成与评价作为多巴胺转运体的潜在 PET 成像剂。
Bioorg Med Chem Lett. 2011 May 15;21(10):2962-5. doi: 10.1016/j.bmcl.2011.03.051. Epub 2011 Mar 21.
2
Synthesis and evaluation of novel tropane derivatives as potential PET imaging agents for the dopamine transporter.新型托烷衍生物的合成与评价作为多巴胺转运体的潜在 PET 成像剂。
Bioorg Med Chem Lett. 2012 Jul 1;22(13):4303-6. doi: 10.1016/j.bmcl.2012.05.030. Epub 2012 May 15.
3
Synthesis and amine transporter affinities of novel phenyltropane derivatives as potential positron emission tomography (PET) imaging agents.
Bioorg Med Chem Lett. 2004 Nov 15;14(22):5635-9. doi: 10.1016/j.bmcl.2004.08.049.
4
Structure-activity relationship studies on a novel series of (S)-2beta-substituted 3alpha-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation.关于一系列新型（S）-2β-取代的3α-[双（4-氟-或4-氯苯基）甲氧基]托烷类似物的构效关系研究，用于体内研究。
J Med Chem. 2006 Oct 19;49(21):6391-9. doi: 10.1021/jm060762q.
5
Synthesis and biological evaluation of a series of novel N- or O-fluoroalkyl derivatives of tropane: potential positron emission tomography (PET) imaging agents for the dopamine transporter.一系列新型托烷N-或O-氟烷基衍生物的合成与生物学评价：用于多巴胺转运体的潜在正电子发射断层扫描（PET）显像剂
Bioorg Med Chem Lett. 2001 Dec 3;11(23):3049-53. doi: 10.1016/s0960-894x(01)00626-6.
6
Synthesis, biodistribution, and primate imaging of fluorine-18 labeled 2beta-carbo-1'-fluoro-2-propoxy-3beta-(4-chlorophenyl)tr opanes. Ligands for the imaging of dopamine transporters by positron emission tomography.氟-18标记的2β-碳-1'-氟-2-丙氧基-3β-(4-氯苯基)托烷的合成、生物分布及灵长类成像。用于正电子发射断层扫描多巴胺转运体成像的配体。
J Med Chem. 2000 Feb 24;43(4):639-48. doi: 10.1021/jm9902234.
7
Synthesis, radiosynthesis, and biological evaluation of carbon-11 and iodine-123 labeled 2beta-carbomethoxy-3beta-[4'-((Z)-2-haloethenyl)phenyl]tropanes: candidate radioligands for in vivo imaging of the serotonin transporter.碳-11和碘-123标记的2β-甲氧羰基-3β-[4'-((Z)-2-卤乙烯基)phenyl]托烷的合成、放射性合成及生物学评价：用于5-羟色胺转运体体内成像的候选放射性配体
J Med Chem. 2004 Feb 26;47(5):1122-35. doi: 10.1021/jm030384e.
8
Fluorinated diaryl sulfides as serotonin transporter ligands: synthesis, structure-activity relationship study, and in vivo evaluation of fluorine-18-labeled compounds as PET imaging agents.作为5-羟色胺转运体配体的氟化二芳基硫醚：氟-18标记化合物作为正电子发射断层显像剂的合成、构效关系研究及体内评价
J Med Chem. 2005 Apr 7;48(7):2559-70. doi: 10.1021/jm0400808.
9
Structure-activity relationship comparison of (S)-2beta-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes and (R)-2beta-substituted 3beta-(3,4-dichlorophenyl)tropanes at the dopamine transporter.多巴胺转运体上(S)-2β-取代的3α-(双[4-氟苯基]甲氧基)托烷和(R)-2β-取代的3β-(3,4-二氯苯基)托烷的构效关系比较
J Med Chem. 2003 Jul 3;46(14):2908-16. doi: 10.1021/jm0300375.
10
Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites.构象受限三环托烷的联芳基类似物作为强效和选择性去甲肾上腺素再摄取抑制剂：其在单胺转运蛋白位点的摄取抑制作用的合成与评价
J Med Chem. 2003 May 8;46(10):1997-2007. doi: 10.1021/jm020596w.
引用本文的文献
1
18F-labelled intermediates for radiosynthesis by modular build-up reactions: newer developments.用于模块化合成反应进行放射性合成的18F标记中间体：新进展
Biomed Res Int. 2014;2014:812973. doi: 10.1155/2014/812973. Epub 2014 Jun 23.
2
Radiosynthesis and validation of ¹⁸F-FP-CMT, a phenyltropane with superior properties for imaging the dopamine transporter in living brain.¹⁸F-FP-CMT的放射性合成及验证，一种具有卓越特性用于活体脑内多巴胺转运体成像的苯基托烷。
J Cereb Blood Flow Metab. 2014 Jul;34(7):1148-56. doi: 10.1038/jcbfm.2014.63. Epub 2014 Apr 9.
本文引用的文献
1
Kinetic analysis and quantification of the dopamine transporter in the nonhuman primate brain with 11C-PE2I and 18F-FE-PE2I.使用 11C-PE2I 和 18F-FE-PE2I 对非人类灵长类动物大脑中的多巴胺转运体进行动力学分析和定量。
J Nucl Med. 2011 Jan;52(1):132-9. doi: 10.2967/jnumed.110.077651.
2
The DAT ligand [(18)F]PR17.MZ mirrors the in vivo pharmacokinetic profile of [(11)C]cocaine with significantly improved monoamine transporter selectivity.多巴胺转运体（DAT）配体[(18)F]PR17.MZ反映了[(11)C]可卡因的体内药代动力学特征，且单胺转运体选择性显著提高。
ChemMedChem. 2010 Oct 4;5(10):1686-8. doi: 10.1002/cmdc.201000237.
3
Synthesis, fluorine-18 radiolabeling, and biological evaluation of N-((E)-4-fluorobut-2-en-1-yl)-2beta-carbomethoxy-3beta-(4'-halophenyl)nortropanes: candidate radioligands for in vivo imaging of the brain dopamine transporter with positron emission tomography.N-((E)-4-氟丁-2-烯-1-基)-2β-羧酸甲酯-3β-(4′-卤代苯基)去甲托品的合成、氟-18 标记及生物学评价：正电子发射断层扫描脑多巴胺转运体体内成像的候选放射性配体。
J Med Chem. 2010 Aug 12;53(15):5549-57. doi: 10.1021/jm100269c.
4
Ex vivo and in vivo evaluation of [18F]PR04.MZ in rodents: a selective dopamine transporter imaging agent.[18F]PR04.MZ在啮齿动物中的体外和体内评估：一种选择性多巴胺转运体显像剂。
ChemMedChem. 2009 Sep;4(9):1480-7. doi: 10.1002/cmdc.200900177.
5
Synthesis, radiolabeling and preliminary in vivo evaluation of [18F]FE-PE2I, a new probe for the dopamine transporter.新型多巴胺转运体探针[18F]FE-PE2I的合成、放射性标记及初步体内评估
Bioorg Med Chem Lett. 2009 Aug 15;19(16):4843-5. doi: 10.1016/j.bmcl.2009.06.032. Epub 2009 Jun 13.
6
2-(2'-((Dimethylamino)methyl)-4'-(3-[(18)F]fluoropropoxy)-phenylthio)benzenamine for positron emission tomography imaging of serotonin transporters.用于5-羟色胺转运体正电子发射断层显像的2-(2'-((二甲氨基)甲基)-4'-(3-[(18)F]氟丙氧基)-苯硫基)苯胺
Nucl Med Biol. 2008 May;35(4):447-58. doi: 10.1016/j.nucmedbio.2008.02.009.
7
Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder.不同基底神经节神经回路中的多巴胺能失衡：对帕金森病、精神分裂症和注意力缺陷多动障碍病理生理学的影响。
Neurotox Res. 2006 Dec;10(3-4):167-79. doi: 10.1007/BF03033354.
8
Identification and regional distribution in rat brain of radiometabolites of the dopamine transporter PET radioligand [11C]PE2I.多巴胺转运体PET放射性配体[11C]PE2I在大鼠脑中放射性代谢物的鉴定及区域分布
Eur J Nucl Med Mol Imaging. 2007 May;34(5):667-678. doi: 10.1007/s00259-006-0277-1. Epub 2006 Nov 10.
9
Role of monoamine transporters in mediating psychostimulant effects.单胺转运体在介导精神兴奋剂作用中的作用。
AAPS J. 2005 Dec 20;7(4):E847-51. doi: 10.1208/aapsj070481.
Zotero 插件