Probst Katrin C, Izquierdo David, Bird Joseph L E, Brichard Laurent, Franck Dominic, Davies John R, Fryer Tim D, Richards Hugh K, Clark John C, Davenport Anthony P, Weissberg Peter L, Warburton Elizabeth A
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, CB2 2QQ Cambridge, UK.
Nucl Med Biol. 2007 May;34(4):439-46. doi: 10.1016/j.nucmedbio.2007.02.009.
The peripheral benzodiazepine receptor (PBR) has shown considerable potential as a clinical marker of neuroinflammation and tumour progression. [(11)C]DAA1106 ([(11)C]N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide) is a promising positron emission tomography (PET) radioligand for imaging PBRs.
A four-step synthetic route was devised to prepare DAA1123, the precursor for [(11)C]DAA1106. Two robust, high yielding methods for radiosynthesis based on [(11)C]-O-methylation of DAA1123 were developed and implemented on a nuclear interface methylation module, producing [(11)C]DAA1106 with up to 25% radiochemical yields at end-of-synthesis based on [(11)C]CH(3)I trapped. Evaluation of [(11)C]DAA1106 for in vivo imaging was performed in a rabbit model with microPET, and the presence of PBR receptor in the target organ was further corroborated by immunohistochemistry.
The standard solution method produced 2.6-5.2 GBq (n=19) of [(11)C]DAA1106, whilst the captive solvent method produced 1.6-6.3 GBq (n=10) of [(11)C]DAA1106. Radiochemical purities obtained were 99% and specific radioactivity at end-of-synthesis was up to 200 GBq/micromol for both methods. Based on radiochemical product, shorter preparation times and simplicity of synthesis, the captive solvent method was chosen for routine productions of [(11)C]DAA1106. In vivo microPET [(11)C]DAA1106 scans of rabbit kidney demonstrated high levels of binding in the cortex. The subsequent introduction of nonradioactive DAA1106 (0.2 micromol) produced considerable displacement of the radioactive signal in this region. The presence of PBR in kidney cortex was further corroborated by immunohistochemistry.
A robust, high yielding captive solvent method of [(11)C]DAA1106 production was developed which enabled efficacious in vivo imaging of PBR expressing tissues in an animal model.
外周苯二氮䓬受体（PBR）作为神经炎症和肿瘤进展的临床标志物已显示出巨大潜力。[(11)C]DAA1106（[(11)C]N-(2,5-二甲氧基苄基)-N-(5-氟-2-苯氧基苯基)-乙酰胺）是一种用于PBR成像的有前景的正电子发射断层扫描（PET）放射性配体。
设计了一条四步合成路线来制备DAA1123，即[(11)C]DAA1106的前体。开发了两种基于DAA1123的[(11)C]-O-甲基化的稳健、高产率的放射性合成方法，并在核界面甲基化模块上实施，基于捕获的[(11)C]CH(3)I，合成结束时[(11)C]DAA1106的放射化学产率高达25%。在兔模型中用微型PET对[(11)C]DAA1106进行体内成像评估，并通过免疫组织化学进一步证实靶器官中PBR受体的存在。
标准溶液法产生了2.6 - 5.2 GBq（n = 19）的[(11)C]DAA1106，而捕获溶剂法产生了1.6 - 6.3 GBq（n = 10）的[(11)C]DAA1106。两种方法获得的放射化学纯度均为99%，合成结束时的比活度高达200 GBq/μmol。基于放射化学产物、更短的制备时间和合成的简便性，选择捕获溶剂法用于[(11)C]DAA1106的常规生产。兔肾的体内微型PET [(11)C]DAA1106扫描显示皮质中有高水平的结合。随后引入非放射性DAA1106（0.2 μmol）导致该区域放射性信号有显著位移。免疫组织化学进一步证实了肾皮质中PBR的存在。
开发了一种稳健、高产率的捕获溶剂法来生产[(11)C]DAA1106，该方法能够在动物模型中对表达PBR的组织进行有效的体内成像。
