College of Chemistry, Beijing Normal University, Beijing 100875, PR China; Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA; Five Eleven Pharma Inc., Philadelphia, PA 19104, USA.
Nucl Med Biol. 2019 May-Jun;72-73:26-35. doi: 10.1016/j.nucmedbio.2019.07.002. Epub 2019 Jul 11.
Recently, a deuterated tracer, D6-[F]FP-(+)-DTBZ, 9-O-hexadeutero-3-[F]fluoropropoxyl-(+)-dihydrotetrabenazine ([F]9), targeting vesicular monoamine transporter 2 (VMAT2) in the central nervous system, was reported as a useful imaging agent for the diagnosis of Parkinson's disease (PD). The production of [F]9 was optimized and simplified by using solid-phase extraction (SPE) purification.
Three major nonradioactive impurities were synthesized and characterized. The preparation of [F]9 was optimized by using different labeling conditions, and an SPE purification method was evaluated. The influence of chemical impurities in the final dose of [F]9 was assessed by an in vitro binding assay, an assay of the in vivo biodistribution in mice, and ex vivo and in vitro autoradiography of brain sections.
Optimized fluorination conditions for [F]9 were found - heating at 130 °C for 10 min in DMSO, and a high radiochemical yield and three major chemical impurities were observed. An SPE method involving a Sep-Pak® tC18 Plus Light cartridge with a two-step elution process was successfully implemented. This process gave a good radiochemical yield (38.7 ± 10.5%, decay corrected; radiochemical purity >99%) and low chemical impurities. An in vivo biodistribution study and autoradiography of brain sections showed that there was no significant difference between HPLC-purified and SPE-purified [F]9.
A VMAT2 targeting imaging agent, D6-[F]FP-(+)-DTBZ, [F]9, was prepared by optimized labeling conditions and an easy SPE purification. This method offers a short preparation time and operational simplicity. In conjunction with PET imaging, this new VMAT2 agent might be a useful clinical tool for diagnosing PD.
最近，一种氘代示踪剂 D6-[F]FP-(+)-DTBZ，即 9-O-全氘代-3-[F]氟丙氧基-(+)-二氢四苯并嗪([F]9)，被报道为一种用于诊断帕金森病（PD）的中枢神经系统囊泡单胺转运体 2（VMAT2）的有用成像剂。通过固相萃取（SPE）纯化，优化并简化了[F]9 的生产。
合成并表征了三种主要的非放射性杂质。通过使用不同的标记条件优化了[F]9 的制备，并评估了 SPE 纯化方法。通过体外结合测定、小鼠体内生物分布测定以及脑切片的体外和体内放射自显影，评估了[F]9 最终剂量中化学杂质的影响。
确定了[F]9 的最佳氟化条件——在 DMSO 中 130°C 加热 10 分钟，同时观察到高放射化学产率和三种主要化学杂质。成功实施了一种涉及 Sep-Pak® tC18 Plus Light 筒的 SPE 方法，该方法采用两步洗脱过程。该过程提供了良好的放射化学产率（38.7±10.5%，衰变校正；放射化学纯度>99%）和低化学杂质。体内生物分布研究和脑切片放射自显影显示，HPLC 纯化和 SPE 纯化的[F]9 之间没有显著差异。
通过优化的标记条件和简单的 SPE 纯化，制备了一种 VMAT2 靶向成像剂 D6-[F]FP-(+)-DTBZ，[F]9。该方法具有较短的制备时间和操作简单的特点。与 PET 成像结合，这种新的 VMAT2 剂可能成为诊断 PD 的有用临床工具。
