Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm 17176, Sweden.
Department of Medicinal Chemistry, Uppsala University, Uppsala 751 05, Sweden.
ACS Chem Neurosci. 2020 Apr 1;11(7):1048-1057. doi: 10.1021/acschemneuro.9b00680. Epub 2020 Mar 24.
The metabotropic glutamate receptor subtype mGluR5 has been proposed as a potential drug target for CNS disorders such as anxiety, depression, Parkinson's disease, and epilepsy. The AstraZeneca compound AZD9272 has previously been labeled with carbon-11 and used as a PET radioligand for mGluR5 receptor binding. The molecular structure of AZD9272 allows one to label the molecule with fluorine-18 without altering the structure. The aim of this study was to develop a fluorine-18 analogue of AZD9272 and to examine its binding distribution in the nonhuman primate brain as well as to obtain whole body radiation dosimetry. F-AZD9272 was successfully synthesized from a nitro precursor. The radioligand was stable, with a radiochemical purity of >99% at 2 h after formulation in a sterile phosphate buffered solution (pH = 7.4). After injection of F-AZD9272 in two cynomolgus monkeys, the maximum whole brain radioactivity concentration was 4.9-6.7% of the injected dose ( = 2) and PET images showed a pattern of regional radioactivity consistent with that previously obtained for C-AZD9272. The percentage of parent radioligand in plasma was 59 and 64% ( = 2) at 120 min after injection of F-AZD9272, consistent with high metabolic stability. Two whole body PET scans were performed in nonhuman primates for a total of 231 min after injection of F-AZD9272. Highest uptakes were seen in liver and small intestine, followed by brain and kidney. The estimated effective dose was around 0.017 mSv/MBq. F-AZD9272 shows suitable properties as a PET radioligand for imaging of binding in the primate brain. F-labeled AZD9272 offers advantages over C-AZD9272 in terms of higher image resolution, combined with a longer half-life. Moreover, based on the distribution and the estimated radiation burden, imaging of F-AZD9272 could be used as an improved tool for quantitative assessment and characterization of AZD9272 binding sites in the human brain by using PET.
代谢型谷氨酸受体亚型 mGluR5 已被提议作为中枢神经系统疾病（如焦虑、抑郁、帕金森病和癫痫）的潜在药物靶点。阿斯利康公司的化合物 AZD9272 之前已被标记上碳-11 并被用作 mGluR5 受体结合的 PET 放射性配体。AZD9272 的分子结构允许人们在不改变结构的情况下用氟-18 标记该分子。本研究的目的是开发一种 AZD9272 的氟-18 类似物，并研究其在非人类灵长类动物脑中的结合分布情况，以及获得全身辐射剂量学数据。F-AZD9272 是从硝基前体成功合成的。放射性配体稳定，在无菌磷酸盐缓冲溶液（pH = 7.4）中配制 2 小时后，放射化学纯度>99%。在两只食蟹猴中注射 F-AZD9272 后，最大全脑放射性浓度为注射剂量的 4.9-6.7%（ = 2），PET 图像显示的放射性分布模式与之前获得的 C-AZD9272 一致。在注射 F-AZD9272 120 分钟后，血浆中母体放射性配体的百分比为 59%和 64%（ = 2），表明其代谢稳定性较高。在注射 F-AZD9272 后总共进行了 2 次非人类灵长类动物的全身 PET 扫描，总时间为 231 分钟。在肝脏和小肠中观察到最高的摄取，其次是大脑和肾脏。估计有效剂量约为 0.017 mSv/MBq。F-AZD9272 作为一种 PET 放射性配体，适合用于灵长类动物大脑结合的成像。与 C-AZD9272 相比，F 标记的 AZD9272 在提高图像分辨率的同时，具有更长的半衰期，具有优势。此外，根据分布和估计的辐射负担，通过 PET 成像，F-AZD9272 的成像可以作为一种改进的工具，用于对人类大脑中 AZD9272 结合位点进行定量评估和表征。
