[18F]AV-133 的改良放射性合成：一种用于囊泡单胺转运体 2 的 PET 成像剂。
An improved radiosynthesis of [18F]AV-133: a PET imaging agent for vesicular monoamine transporter 2.
机构信息
Key Laboratory of Radiopharmaceuticals, Beijing Normal University, Ministry of Education, Beijing 100875, PR China.
出版信息
Nucl Med Biol. 2010 Feb;37(2):133-41. doi: 10.1016/j.nucmedbio.2009.10.005. Epub 2009 Dec 16.
INTRODUCTION
Recently, a PET tracer, 9-[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133), targeting vesicular monoamine transporter 2 (VMAT2) in the central nervous system has been reported. It is currently under Phase II clinical trials to establish its usefulness in the diagnosis of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. The radiolabeling of [(18)F]AV-133, nucleophilic fluorination reaction and potential effects of pseudo-carrier were evaluated by in vivo biodistribution.
METHODS
The preparation of [(18)F]AV-133 was evaluated under different conditions, specifically by employing different precursors (-OTs or -Br as the leaving group at the 9-propoxy position), reagents (K222/K(2)CO(3) vs. tributylammonium bicarbonate) and solvents (acetonitrile vs. DMSO), reaction temperature and reaction time. With optimized conditions from these experiments, radiosynthesis and purification with solid-phase extraction (SPE) of [(18)F]AV-133 were performed by an automated nucleophilic [(18)F]fluorination module. In vivo biodistribution in mice on [(18)F]AV-133 purified by either HPLC (no-carrier-added) or the SPE method (containing a pseudo-carrier) was performed and the results compared.
RESULTS
Under a mild fluorination condition (heating at 115 degrees C for 5 min in dimethyl sulfoxide), [(18)F]AV-133 was obtained in a high yield using either -OTs or -Br as the leaving group. However, the -OTs precursor gave better radiochemical yields (>70%, thin layer chromatography analysis) compared to those of the -Br precursor. The optimized reaction conditions were successfully implemented to an automated nucleophilic fluorination module. Labeling and purification of [(18)F]AV133 were readily achieved via this automatic module in good radiochemical yield of 21-41% (n=10) in 40 min. The radiochemical purity was larger than 95%. Biodistribution of SPE-purified product (containing a pseudo-carrier) in mice showed a high striatum/cerebellum ratio (4.18+/-0.51), which was comparable to that of HPLC-purified [(18)F]AV-133 (4.51+/-0.10).
CONCLUSIONS
The formation of [(18)F]AV-133 was evaluated under different labeling conditions. These improved labeling conditions and SPE purification were successfully implemented into an automated synthesis module. This offers a short preparation time (about 40 min), simplicity in operation and ready applicability for routine clinical operation.
简介
最近，一种用于检测中枢神经系统囊泡单胺转运体 2（VMAT2）的正电子发射断层扫描（PET）示踪剂 9-[[18]F]氟丙基-（+）-二氢四苯并嗪（[18]F]AV-133）已被报道。目前正在进行 II 期临床试验，以确定其在包括路易体痴呆和帕金森病在内的神经退行性疾病诊断中的作用。通过体内生物分布评估了[18]F]AV-133 的放射性标记、亲核氟化反应和伪载剂的潜在影响。
方法
通过不同的条件评估[18]F]AV-133 的制备情况，特别是使用不同的前体（-OTs 或 -Br 作为 9-丙氧基位置的离去基团）、试剂（K222/K（2）CO3 与三丁基碳酸氢铵）和溶剂（乙腈与 DMSO）、反应温度和反应时间。根据这些实验的优化条件，通过自动化亲核[18]F 氟化模块进行[18]F]AV-133 的放射性合成和固相萃取（SPE）纯化。通过高效液相色谱（无载体添加）或 SPE 方法（含有伪载体）纯化的[18]F]AV-133 在小鼠体内的分布情况，并进行比较。
结果
在温和的氟化条件下（在二甲基亚砜中 115℃加热 5 分钟），使用 -OTs 或 -Br 作为离去基团，[18]F]AV-133 的产率都很高。然而，与 -Br 前体相比，-OTs 前体的放射化学产率更高（>70%，薄层层析分析）。优化的反应条件成功地应用于自动化亲核氟化模块。通过该自动模块，[18]F]AV133 的标记和纯化可以在 40 分钟内以 21-41%的良好放射化学产率（n=10）轻易实现，放射化学纯度大于 95%。在小鼠中，SPE 纯化产物（含有伪载体）的生物分布显示出很高的纹状体/小脑比（4.18+/-0.51），与 HPLC 纯化的[18]F]AV-133（4.51+/-0.10）相当。
结论
在不同的标记条件下评估了[18]F]AV-133 的形成。这些改进的标记条件和 SPE 纯化已成功地应用于自动化合成模块。这提供了一个较短的制备时间（约 40 分钟），操作简单，便于常规临床应用。
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