Radiosynthesis of N-(4-chloro-3-[(11)C]methoxyphenyl)-2-picolinamide ([(11)C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4).
Radiosynthesis of N-(4-chloro-3-[(11)C]methoxyphenyl)-2-picolinamide ([(11)C]ML128) as a PET radiotracer for metabotropic glutamate receptor subtype 4 (mGlu4).
复制标题
N-(4-氯-3-[(11)C]甲氧基苯基)-2-吡啶甲酰胺 ([(11)C]ML128) 的放射合成作为代谢型谷氨酸受体亚型 4 (mGlu4) 的 PET 放射性示踪剂。
DOI：
10.1016/j.bmc.2013.07.046
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发表时间：
2013
影响因子：
3.5
通讯作者：
Brownell,Anna-Liisa
中科院分区：
文献类型：
--
作者：
Kil,Kun-Eek;Zhang,Zhaoda;Jokivarsi,Kimmo;Gong,Chunyu;Choi,Ji-Kyung;Kura,Sreekanth;Brownell,Anna-Liisa
N-(Chloro-3-methoxyphenyl)-2-picolinamide （3, ML128, VU0361737）是一种强效且具有中心穿透性的mglu4阳性变构调节剂（PAM）。3也是第一个在临床前帕金森病模型中显示出全身给药疗效的mGlu4PAM。作为一种无创医学成像技术和神经学研究的有力工具，正电子发射断层扫描（PET）为研究mglu4在生理和病理条件下的表达提供了可能。我们合成了碳-11标记的ML128 （[11C]3）作为mGlu4的PET示踪剂，并对其在Sprague Dawley大鼠体内的生物学特性进行了表征。以[11C]CH3I为原料，由n -（4-氯-3-羟基苯基）-2-吡啶酰胺(2)合成[11C]3。从轰击结束到配方的总合成时间为38±2.2 min （n= 7）。根据[11C]CO2的放射性，以27.7±5.3% （n= 5）的衰变校正放射化学产率得到放射性配体[11C]3。[11C]3的放射化学纯度为99%。合成结束时比活性为188.7±88.8 GBq/mol （n= 4）。对20只正常雄性Sprague Dawley大鼠进行PET成像，其中11只为对照，6只为mglu5调节剂阻断(4)研究特异性，3只为mglu5调节剂（MTEP）阻断研究选择性。这些研究表明，在纹状体、丘脑、海马、小脑和嗅球等几个脑区，[11C]3在快速冲洗后迅速积累（峰值活动在1-3分钟之间）。mglu4modulator4的阻断研究显示，[11C]3的积累减少了22-28%，而选择性研究显示，与mGlu5相比，[11C]3的积累只减少了少量，这表明mGlu5具有良好的选择性。生物分布研究和血液分析支持快速代谢。总之，这是mGlu4的第一个PET成像配体，其中标记的ML128用于成像其体内分布和脑内药代动力学。
N-(Chloro-3-methoxyphenyl)-2-picolinamide (3, ML128, VU0361737) is an mGlu4positive allosteric modulator (PAM), which is potent and centrally penetrating.3is also the first mGlu4PAM to show efficacy in a preclinical Parkinson disease model upon systemic dosing. As a noninvasive medical imaging technique and a powerful tool in neurological research, positron emission tomography (PET) offers a possibility to investigate mGlu4expressionin vivounder physiologic and pathological conditions. We synthesized a carbon-11 labeled ML128 ([11C]3) as a PET radiotracer for mGlu4, and characterized its biological properties in Sprague Dawley rats. [11C]3was synthesized fromN-(4-chloro-3-hydroxyphenyl)-2-picolinamide (2) using [11C]CH3I. Total synthesis time was 38 ± 2.2 min (n= 7) from the end of bombardment to the formulation. The radioligand [11C]3was obtained in 27.7 ± 5.3% (n= 5) decay corrected radiochemical yield based on the radioactivity of [11C]CO2. The radiochemical purity of [11C]3was >99%. Specific activity was 188.7 ± 88.8 GBq/mol (n= 4) at the end of synthesis (EOS).PET images were conducted in 20 normal male Sprague Dawley rats including 11 control studies, 6 studies blocking with an mGlu4modulator (4) to investigate specificity and 3 studies blocking with an mGlu5modulator (MTEP) to investigate selectivity. These studies showed fast accumulation of [11C]3(peak activity between 1–3 min) in several brain areas including striatum, thalamus, hippocampus, cerebellum, and olfactory bulb following with fast washout. Blocking studies with the mGlu4modulator4showed 22–28% decrease of [11C]3accumulation while studies of selectivity showed only minor decrease supporting good selectivity over mGlu5. Biodistribution studies and blood analyses support fast metabolism. Altogether this is the first PET imaging ligand for mGlu4, in which the labeled ML128 was used for imaging itsin vivodistribution and pharmacokinetics in brain.