Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, United States.
Bioorg Med Chem. 2013 Oct 1;21(19):5955-62. doi: 10.1016/j.bmc.2013.07.046. Epub 2013 Aug 2.
N-(Chloro-3-methoxyphenyl)-2-picolinamide (3, ML128, VU0361737) is an mGlu4 positive allosteric modulator (PAM), which is potent and centrally penetrating. 3 is also the first mGlu4 PAM 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 mGlu4 expression in vivo under physiologic and pathological conditions. We synthesized a carbon-11 labeled ML128 ([(11)C]3) as a PET radiotracer for mGlu4, and characterized its biological properties in Sprague Dawley rats. [(11)C]3 was synthesized from N-(4-chloro-3-hydroxyphenyl)-2-picolinamide (2) using [(11)C]CH3I. Total synthesis time was 38±2.2min (n=7) from the end of bombardment to the formulation. The radioligand [(11)C]3 was obtained in 27.7±5.3% (n=5) decay corrected radiochemical yield based on the radioactivity of [(11)C]CO2. The radiochemical purity of [(11)C]3 was >99%. Specific activity was 188.7±88.8GBq/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 mGlu4 modulator (4) to investigate specificity and 3 studies blocking with an mGlu5 modulator (MTEP) to investigate selectivity. These studies showed fast accumulation of [(11)C]3 (peak activity between 1-3min) in several brain areas including striatum, thalamus, hippocampus, cerebellum, and olfactory bulb following with fast washout. Blocking studies with the mGlu4 modulator 4 showed 22-28% decrease of [(11)C]3 accumulation 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 its in vivo distribution and pharmacokinetics in brain.
N-(氯-3-甲氧基苯基)-2-吡啶甲酰胺（3，ML128，VU0361737）是一种 mGlu4 正变构调节剂（PAM），具有强大的中枢穿透能力。3 也是第一个在系统给药后在临床前帕金森病模型中显示疗效的 mGlu4 PAM。作为一种非侵入性医学成像技术和神经科学研究的强大工具，正电子发射断层扫描（PET）提供了一种在生理和病理条件下研究体内 mGlu4 表达的可能性。我们合成了一种碳-11 标记的 ML128([(11)C]3)作为 mGlu4 的 PET 示踪剂，并在 Sprague Dawley 大鼠中表征了其生物学特性。[(11)C]3 是由 N-(4-氯-3-羟基苯基)-2-吡啶甲酰胺（2）用[(11)C]CH3I 合成的。从末位到制剂的总合成时间为 38±2.2min(n=7)。[(11)C]3 的放射性配体在 5 次衰变校正放射性化学产率中以 27.7±5.3%（n=5）获得，基于[(11)C]CO2 的放射性。[(11)C]3 的放射化学纯度>99%。在合成结束时（EOS），比活度为 188.7±88.8GBq/mol（n=4）。在 20 只正常雄性 Sprague Dawley 大鼠中进行了 PET 成像，包括 11 项对照研究、6 项用 mGlu4 调节剂（4）阻断以研究特异性和 3 项用 mGlu5 调节剂（MTEP）阻断以研究选择性的研究。这些研究表明，[(11)C]3（1-3min 之间的峰值活性）在包括纹状体、丘脑、海马、小脑和嗅球在内的几个脑区快速积累，随后快速清除。用 mGlu4 调节剂 4 进行的阻断研究显示，[(11)C]3 积累减少了 22-28%，而选择性研究显示，只有轻微减少，表明对 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。总的来说，这是第一个用于 mGlu4 的 PET 成像配体，其中标记的 ML128 用于成像其在大脑中的体内分布和药代动力学。
