Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1
Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1
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DOI：
10.1021/acschemneuro.8b00183
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发表时间：
2018-11-01
影响因子：
5
通讯作者：
Kilbourn, Michael R.
中科院分区：
文献类型：
--
作者：
Sowa, Alexandra R.;Brooks, Allen F.;Kilbourn, Michael R.
γ-氨基丁酸（GABA）受体复合物的体内正电子发射断层扫描（PET）成像已使用放射性标记的苯二氮卓衍生物完成，但针对神经元膜GABA转运蛋白1型（GAT-1）的特异性突触前放射性配体的开发不太成功。GAT-1抑制剂的新的结构-活性研究的可用性和GAT-1抑制剂（噻加宾，Gabatril）引入临床使用促使我们重新研究这种转运蛋白的PET配体的合成。N-[C-11]甲基哌啶甲酸的初始合成和啮齿动物PET研究证实了该小极性分子的低脑摄取。改善GAT-1抑制剂的血脑屏障渗透性的常见设计方法是连接大的亲脂性取代基。我们选择了一个不对称的双芳族残基连接到环氮的乙烯基醚间隔从一系列最近报道的Wanner和同事。使用芳基氯前体与[F-18]氟化物的亲核芳族取代来制备期望的候选放射性示踪剂（R，E/Z）-1-（2-（（4-氟-2-（4-[F-18] ㈠氟苯甲酰基）苯乙烯基）氧基）乙基）-哌啶-3-甲酸（（R，E/Z）-[F-18]10）。大鼠的PET研究显示没有脑摄取，这并没有改变与P-糖蛋白抑制剂环孢素A的动物预处理，表明Pgp的流出是不负责。随后在恒河猴脑中对（R，E/Z）-[F-18]10进行的PET成像研究显示脑摄取非常低。最后，为了测试游离羧酸基团是否是脑摄取不良的可能原因，使用（R，E/Z）-[F-18]10的乙酯衍生物进行PET研究。快速和显着的猴脑摄取的酯，随后由一个缓慢的冲洗超过90分钟。血脑屏障的酯的渗透性支持一个假设，即游离酸功能限制脑摄取的哌啶甲酸为基础的GAT-1放射性配体，和未来的放射性示踪剂的努力应该调查使用羧酸生物电子等排体。
In vivo positron emission tomography (PET) imaging of the gamma-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radio-ligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[C-11]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [F-18]fluoride was used to prepare the desired candidate radiotracer (R,E/Z)-1-(2-((4-fluoro-2-(4-[F-18](-)uorobenzoyl)styryl)oxy)ethyl)-piperidine-3-carboxylic acid ((R,E/Z)-[F-18]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of (R,E/Z)-[F-18]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of (R,E/Z)-[F-18]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.