Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan; SHI Accelerator Service Co., 1-17-6 Osaki, Shinagawa-ku, Tokyo 141-0032, Japan.
Bioorg Med Chem. 2018 Sep 15;26(17):4817-4822. doi: 10.1016/j.bmc.2018.08.017. Epub 2018 Aug 12.
DAA1106 (N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide), is a potent and selective ligand for the translocator protein (18 kDa, TSPO) in brain mitochondrial fractions of rats and monkey (K = 0.043 and 0.188 nM, respectively). In this study, to translate [F]DAA1106 for clinical studies, we performed automated syntheses of [F]DAA1106 using the spirocyclic iodonium ylide (1) as a radiolabelling precursor and conducted preclinical studies including positron emission tomography (PET) imaging of TSPO in ischemic rat brains. Radiofluorination of the ylide precursor 1 with [F]F, followed by HPLC separation and formulation, produced the [F]DAA1106 solution for injection in 6% average (n = 10) radiochemical yield (based on [F]F) with >98% radiochemical purity and molar activity of 60-100 GBq/μmol at the end of synthesis. The synthesis time was 87 min from the end of bombardment. The automated synthesis achieved [F]DAA1106 with sufficient radioactivity available for preclinical and clinical use. Biodistribution study of [F]DAA1106 showed a low uptake of radioactivity in the mouse bones. Metabolite analysis showed that >96% of total radioactivity in the mouse brain at 60 min after the radiotracer injection was unmetabolized [F]DAA1106. PET study of ischemic rat brains visualized ischemic areas with a high uptake ratio (1.9 ± 0.3) compared with the contralateral side. We have provided evidence that [F]DAA1106 could be routinely produced for clinical studies.
DAA1106（N-(2,5-二甲氧基苄基）-N-(5-氟-2-苯氧基苯基）乙酰胺），是大鼠和猴脑线粒体部分中跨膜蛋白（18 kDa，TSPO）的一种有效且选择性的配体（K 值分别为 0.043 和 0.188 nM）。在这项研究中，为了将 [F]DAA1106 用于临床研究，我们使用螺环碘化𬭩叶立德（1）作为放射性标记前体，进行了 [F]DAA1106 的自动化合成，并进行了包括 TSPO 在缺血性大鼠脑内的正电子发射断层扫描（PET）成像在内的临床前研究。叶立德前体 1 与 [F]F 的放射性氟化反应，然后通过 HPLC 分离和制剂，以 6%的平均（n=10）放射化学产率（基于 [F]F）生产出 [F]DAA1106 注射液，放射化学纯度>98%，合成结束时摩尔活度为 60-100GBq/μmol。从结束辐照到合成完成的总时间为 87 分钟。自动化合成实现了 [F]DAA1106 的放射性活性，足以用于临床前和临床应用。[F]DAA1106 的生物分布研究表明，放射性核素在小鼠骨骼中的摄取率较低。代谢产物分析表明，在注射示踪剂后 60 分钟，小鼠脑内的总放射性活性中，未经代谢的 [F]DAA1106 超过 96%。对缺血性大鼠脑的 PET 研究显示，与对侧相比，缺血区域的摄取比值（1.9±0.3）较高。我们已经提供了证据表明，[F]DAA1106 可以常规生产用于临床研究。
