Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, Massachusetts 02129, United States.
Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
J Med Chem. 2022 Jul 28;65(14):9939-9954. doi: 10.1021/acs.jmedchem.2c00593. Epub 2022 Jul 8.
An array of triazolopyridines based on JNJ-46356479 () were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound in the cAMP GloSensor assays. Radiolabeling of compounds and (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/μmol; and excellent radiochemical purity, >98%. Preliminary characterization of [F] and [F] in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [F] in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [F]. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [F]. As a selective ligand, [F] has the potential to be developed for translational studies.
基于 JNJ-46356479 的一系列三唑并吡啶类化合物被合成出来，作为代谢型谷氨酸受体 2（mGluR2）的正电子发射断层扫描（PET）放射性示踪剂。与 cAMP GloSensor 测定中的化合物相比，所选候选化合物的正变构调节剂（PAM）活性（最大 20 倍）和 mGluR2 激动剂活性（最大 25 倍）均得到增强。通过 Cu 介导的放射性氟化反应对化合物 和 （mG2P026）进行放射性标记，获得了令人满意的放射化学产率（>5%，未经衰变校正）、高摩尔活性（>180GBq/μmol）和优异的放射化学纯度（>98%）。[F]和[F]在大鼠中的初步特性研究证实了它们具有出色的脑渗透性和结合动力学。在非人类灵长类动物中对[F]的进一步评估证实，其在 mGluR2 图谱中具有更高的脑异质性和比[F]更高的亲和力。在大鼠和灵长类动物中用不同类别的 PAMs 预处理后，[F]的脑摄取量也得到了类似的增强。作为一种选择性配体，[F]有可能被开发用于转化研究。
