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68Ga‐Labelled Tropane Analogues for the Visualization of the Dopaminergic System
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-27 , DOI: 10.1002/cmdc.202000820
Sascha Häseli 1 , Marion Holy 2 , Markus Joksch 3 , Carina Bergner 3 , Andreas Wree 4 , Jens Kurth 3 , Aylin Cankaya 1 , Markus Piel 1 , Bernd J Krause 3 , Harald H Sitte 2 , Frank Rösch 1
Affiliation  

The development of radiometal‐labelled pharmaceuticals for neuroimaging could offer great potential due to easier handling during labelling and availability through radionuclide generator systems. Nonetheless, to date, no such tracers are available for positron emission tomography, primarily owing to the challenge of crossing the blood–brain barrier (BBB) and loss of affinity through chelator attachment. We have prepared a variety of 68Ga‐labelled phenyltropanes showing that, through a simple hydrocarbon‐linker, it is possible to introduce a chelator onto the lead structure while maintaining its high affinity for hDAT (human dopamine transporter) and simultaneously achieving adequate lipophilicity. One of the candidates, [68Ga]Ga‐HBED‐hexadiyne‐tropane, showed an IC50 value of 66 nM, together with a log D7.4 of 0.96. A μPET study in a hemi‐parkinsonian rat model showed a fast wash‐out of the tracer, and no specific uptake in the brain, thus implying an inability to penetrate the BBB.

中文翻译:

68Ga 标记的托烷类似物用于多巴胺能系统的可视化

用于神经影像学的放射性金属标记药物的开发可能会提供巨大的潜力,因为标记过程中更容易处理并且可以通过放射性核素发生器系统获得。尽管如此,迄今为止,还没有此类示踪剂可用于正电子发射断层扫描,这主要是由于穿越血脑屏障(BBB)的挑战以及通过螯合剂附着而丧失亲和力。我们制备了多种68 Ga 标记的苯托烷,表明通过简单的烃连接体,可以在先导结构上引入螯合剂,同时保持其对 hDAT(人多巴胺转运蛋白)的高亲和力,同时实现足够的亲脂性。其中一种候选物[ 68 Ga]Ga-HBED-己二炔-托烷的IC 50值为66 nM,log  D 7.4为0.96。对偏侧帕金森病大鼠模型进行的 μPET 研究显示,示踪剂被快速冲走,并且大脑中没有特异性摄取,因此意味着无法穿透血脑屏障。
更新日期:2020-11-27
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