CHARACTERIZATION OF [C-11] TETRABENAZINE AS AN IN-VIVO RADIOLIGAND FOR THE VESICULAR MONOAMINE TRANSPORTER
CHARACTERIZATION OF [C-11] TETRABENAZINE AS AN IN-VIVO RADIOLIGAND FOR THE VESICULAR MONOAMINE TRANSPORTER
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DOI：
10.1016/0969-8051(94)90003-5
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发表时间：
1994-02-01
影响因子：
3.1
通讯作者：
KILBOURN, MR
中科院分区：
文献类型：
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作者：
DASILVA, JN;CAREY, JE;KILBOURN, MR
[C-11]丁苯那嗪（[C-11]TBZ）是一种新的用于囊泡单胺转运体正电子发射断层显像的体内放射性配体。已在啮齿动物中测定了[C-11]TBZ的体内分布、代谢和药理学特异性。[C-11]TBZ在具有最大单胺能神经支配的脑区（纹状体、下丘脑）中的局部小鼠脑保留最高，并且可以用单胺囊泡转运蛋白（TBZ，酮色林）的配体而不是氟哌啶醇（一种多巴胺D受体拮抗剂）降低。大鼠血液的色谱分析表明，[C-11]TBZ快速代谢为放射性标记的代谢物（α-和β-[C-11]二氢丁苯那嗪），这是由于2-酮基还原所致。这些代谢物以及第三种潜在代谢物9-O-去甲基TBZ以未标记形式合成，所有三种代谢物均显示能够大大降低[C-11]TBZ在小鼠纹状体和下丘脑中的体内蓄积。在大鼠中测定注射[C-11]TBZ后放射性的全身生物分布，并使用数据计算该放射性示踪剂的预期人体剂量。这些研究表明，[C-11]TBZ可以安全地用于活体人脑中囊泡单胺转运蛋白的体内PET成像和半定量测定，但放射性分布的定量药代动力学建模将因存在非活性代谢物而变得复杂。
[C-11]Tetrabenazine ([C-11]TBZ) is a new in vivo radioligand for positron emission tomographic (PET) imaging of vesicular monoamine transporters. The in vivo distribution, metabolism and pharmacological specificity of [C-11]TBZ has been determined in rodents. Regional mouse brain retention of [C-11]TBZ is highest in brain regions with greatest monoaminergic innervation (striatum, hypothalamus) and can be reduced with ligands for the monoamine vesicular transporter (TBZ, ketanserin) but not haloperidol, a dopamine D, receptor antagonist. Chromatographic analysis of rat blood demonstrated rapid metabolism of [C-11]TBZ to radiolabeled metabolites (alpha- and beta-[C-11]dihydrotetrabenazine) resulting from reduction of the 2-keto group. These metabolites, as well as a third potential metabolite, 9-O-desmethylTBZ, have been synthesized in unlabeled form and all three were shown to be capable of greatly reducing in vivo accumulation of [C-11]TBZ in mouse striatum and hypothalamus. Whole body biodistribution of radioactivity after [C-11]TBZ injection was determined in rats, and the data used to calculate the expected human dosimetry from this radiotracer. These studies demonstrated that [C-11]TBZ can be safely administered for in vivo PET imaging and semi-quantitative determination of vesicular monoamine transporters in living human brain, but quantitative pharmacokinetic modeling of radioactivity distribution will be complicated by the presence of pharmacologically active metabolites.