正电子发射断层扫描（PET）可以利用正电子核素标记的示踪剂揭示人体内生理代谢过程，是疾病诊断的重要成像技术。¹⁸F正电子核素（半衰期 = 109.77 min）具有优良的核素性质，被广泛用于PET示踪剂研究。¹⁸F标记的示踪剂通常由亲核取代反应制得，其首要步骤是制备高亲核活性的[¹⁸F]F^-（例如：[K2.2.2K][¹⁸F]F）。蒸发除水（共沸干燥）的传统氟化试剂[K2.2.2K][¹⁸F]F的制备方法繁琐耗时，因此，室温下快速高效的制备高活性[¹⁸F]F^-成为放射性药物标记化学研究的热点。同时，由于避免蒸发除水将有利于减少标记过程中的有机溶剂挥发，符合绿色化学发展方向。

本文设计制备新型[K2.2.2K]₂CO₃冠醚金属络合物及其乙腈溶液（含水量小于2%）代替传统方法中的K2.2.2/K₂CO₃和乙腈/水混合溶液（含水量通常大于15%），同时采用自制mini-QMA固相小柱和新的淋洗工艺，无需共沸干燥即可获得高反应活性的[K2.2.2K][¹⁸F]F，并将其成功应用于一个¹⁸F化合物（[¹⁸F]F-NEP）和三个¹⁸F药物（[¹⁸F]FDG、[¹⁸F]AV-45和[¹⁸F]FMISO）的制备；采用上述氟化试剂和新工艺在BIBD-F自动化合成装置上制备[¹⁸F]AV-45。研究内容和结果如下：

一、¹⁸F氟化试剂[K2.2.2K][¹⁸F]F制备新方法

1. 冠醚金属络合物[K2.2.2K]₂CO₃的制备及其含水量的测定

设计合成冠醚金属络合物[K2.2.2K]₂CO₃，并对其进行结构表征。使用Perkin-Elmer Diamond SII热分析仪测定含水量，热重分析（TGA）曲线结果表明：在80 ℃ - 120 ℃时的水分子重量损失约为1.5% - 2%（n = 3）。在放射性标记实验中，冠醚金属络合物的物质的量约为10^-5 mol，其中含水量约为10^-6 mol，微量的水（< 0.1%）对氟化反应产率没有明显影响。

2. 室温下¹⁸F氟化试剂[K2.2.2K][¹⁸F]F的制备 

将加速器制备的[¹⁸F]F^-水溶液通过含有25 mg SEP-Pak^?Light QMA树脂的自制阴离子交换柱（mini-QMA小柱），随后用无水乙腈洗涤，并用空气吹干小柱，最后用0.5 mL含有13 mg [K2.2.2K]₂CO₃的乙腈/水（500 μL/5 μL，V/V）溶液洗脱小柱得到氟化试剂[K2.2.2K][¹⁸F]F。结果显示：当淋洗液含水量为1%，初始活度为37 - 259 MBq时，淋洗率为91% - 99%（n = 43）；当活度增加至1480 MBq时，淋洗率稳定在85% - 86%（n = 3），淋洗效率满足进一步氟化反应的要求。

二、新¹⁸F氟化试剂[K2.2.2K][¹⁸F]F的应用

采用上述方法制备的[K2.2.2K][¹⁸F]F成功标记了一个¹⁸F化合物[¹⁸F]F-NEP和三个¹⁸F药物[¹⁸F]FDG、[¹⁸F]AV-45和[¹⁸F]FMISO。将[K2.2.2K][¹⁸F]F乙腈/水溶液（500 μL/5 μL，V/V）直接加入到[¹⁸F]F-NEP、[¹⁸F]FDG、[¹⁸F]AV-45或[¹⁸F]FMISO的标记前体中，分别在不同有机溶剂和温度下进行亲核氟化反应。结果显示：[¹⁸F]F-NEP的氟化反应产率为73.6 ± 2.7%（n = 3，radio-TLC测定）；标记中间体[¹⁸F]FDG-Ac4、[¹⁸F]AV-45-Boc和[¹⁸F]FMISO-THP的氟化反应产率分别为56.2 ± 1.6%（n = 4），46.9 ± 3.4%（n = 4）和13.1 ± 2.4%（n = 3）。以上结果表明：新型¹⁸F氟化试剂[K2.2.2K][¹⁸F]F可用于PET示踪剂制备。

采用上述新方法制备¹⁸F氟化试剂，在BIBD-F自动化合成装置上成功制备[¹⁸F]AV-45（n = 10）：初始活度为37 - 259 MBq，标记用时约39 min，产品放射化学产率（RCY）为46.5 ± 7.6%（经衰变校正），放射化学纯度（RCP）均大于95%。

本论文通过制备新型[K2.2.2K]₂CO₃冠醚金属络合物，联合使用自制mini-QMA小柱，在室温下（无需共沸干燥）建立制备高亲核反应活性的氟化试剂[K2.2.2K][¹⁸F]F的新方法和新工艺，该方法省略了蒸发除水步骤，快速高效，并成功应用于一个¹⁸F化合物和三个¹⁸F药物的标记，初步建立了[¹⁸F]AV-45的自动化合成新工艺。该方法有望应用于更多的¹⁸F药物标记。

Positron emission tomography (PET) imaging in conjunction with radiotracers labeled with β⁺-emitting nuclide is a powerful technique for diagnosis of various diseases at the molecular level. Fluorine-18 (half-life = 109.77 min) with its excellent nuclear properties is widely used for labeling PET tracers (often referred to as molecular probes or radiopharmaceuticals). In order to prepare ¹⁸F-labeled tracers, it is necessary to create anhydrous condition for a nucleophilic substitution reaction. The first requirement is to "activate" [¹⁸F]F^- (formation of [K2.2.2K][¹⁸F]F) by removing water molecules tightly surrounding the fluoride ion. The traditional preparation method is accomplished through a relatively slow and time-consuming evaporation of water and acetonitrile (azeotropic drying). Therefore, the preparation of highly active [K2.2.2K][¹⁸F]F at room temperature has become the first and foremost the major obstacle to overcome. There is an urgent need to develop optimal procedure to quickly activate fluoride, under which the desired radiochemistry reactions can be readily carried out.

In this thesis, a combination of crown ether metal complex ([K2.2.2K]₂CO₃) and its acetonitrile solution (containing less than 2% of water) were devised as a replacement for the traditional employed K2.2.2/acetonitrile and K₂CO₃/water mixed solution (in which the water content usually was more than 15%). Initially, [¹⁸F]F^- eluted from target was loaded onto a custom-made mini-QMA cartridge containing (25 mg of sold support). Using a new eluting solvent containing minimum amount of water in the acetonitrile as the solvent, [K2.2.2K][¹⁸F]F in wet acetonitrile without azeotropic drying can be accomplished. The eluted [K2.2.2K][¹⁸F]F in wet/acetonitrile was successfully reacted with a model compound, [¹⁸F]F-NEP, and three radiopharmaceuticals, [¹⁸F]FDG, [¹⁸F]AV-45 and [¹⁸F]FMISO. The research contents and results are as follows:

1. A new method for the preparation of activated [K2.2.2K][¹⁸F]F

(1.1) Preparation of crown ether metal complex ([K2.2.2K]₂CO₃) and determination of water content in the acetonitrile as elution solvent.

A crown ether potassium complex ([K2.2.2K]₂CO₃ in solid form) was prepared, and its structure was characterized. The water content of this crown ether complex was determined by a Perkin-Elmer Diamond SII thermal analyzer. Results of thermogravimetric analysis (TGA) showed that the weight loss, due to removing of water molecules, between 80°C - 120°C, was 1.5% - 2% (n = 3). The level of water content in the solid form of [K2.2.2K]₂CO₃ appeared to be quite consistent and apparently, this level of water content in the [K2.2.2K]₂CO₃ complex showed no observable effect on the efficiency of the fluorination reaction. 

(1.2) Preparation of [K2.2.2K][¹⁸F]F at room temperature

The [¹⁸F]F^-/[¹⁸O]H₂O aqueous solution obtained by elution of the target from cyclotron was loaded on a custom-made anion exchange cartridge containing 25 mg of standard SEP-Pak^?Light QMA resin (mini-QMA cartridge). This cartridge was washed with anhydrous acetonitrile and then dried with a stream of air flow for one minute. Finally, a solution of 13 mg [K2.2.2K]₂CO₃ dissolved in 1% water/acetonitrile (V/V, 1/99) was used to elute the [¹⁸F]F^- adsorbed on the cartridge to obtain the desired "activated" [K2.2.2K][¹⁸F]F. The efficiency of [¹⁸F]fluoride recovery was 91% - 99% (n = 43) when the initial activity was between 37 - 259 MBq. When the loaded activity was increased to higher levels - 1480 MBq, the recovery efficiency was slightly lower at 85% - 86% (n = 3). The elution efficiency was sufficient for testing further fluorination reactions.

2. The application of the new [K2.2.2K][¹⁸F]F 

The [K2.2.2K][¹⁸F]F obtained from the method described above was used to test the fluorination reaction between a model compound and three commonly used PET imaging agents. Acetonitrile solution containing [K2.2.2K][¹⁸F]F was directly mixed with the precursor of [¹⁸F]F-NEP, [¹⁸F]FDG, [¹⁸F]AV-45 or [¹⁸F]FMISO, dissolved in different organic solvents. The nucleophilic fluorination reactions were tested at different temperature. [¹⁸F]F-NEP, [¹⁸F]FDG-Ac4, [[¹⁸F]AV-45-Boc and [¹⁸F]FMISO-THP were obtained in fluorination yields of 73.6 ± 2.7% (n = 3), 56.2 ± 1.6% (n = 4), 46.9 ± 3.4% (n = 4), and 13.1 ± 2.4% (n = 3), respectively. Results demonstrated that this new method using [K2.2.2K][¹⁸F]F in wet/acetonitrile was successful for preparing fluorine-18 labeled agents and it was worth exploring further in using this method for preparation of other radiopharmaceuticals.

This wet acetonitrile solution containing [K2.2.2K][¹⁸F]F was also employed to prepare [¹⁸F]AV-45 on an automated synthesis device (BIBD-F). The automated synthesis of [¹⁸F]AV-45 were carefully tested ten times. When the initial [¹⁸F]F^- activity was 37 - 259 MBq, the reaction showed radiochemical yield of 46.5 ± 7.6% (decay corrected) in 40 min, and the radiochemical purity was more than 95%.

In summary, improvement of fluorination reaction using wet acetonitrile solution containing [K2.2.2K][¹⁸F]F for preparation of commonly used radiopharmaceuticals was accomplished. Initially, a new crown ether metal complex [K2.2.2K]₂CO₃ was prepared and a mini-QMA cartridge was employed to trapped [K2.2.2K][¹⁸F]F in wet/acetonitrile (without azeotropic drying). The fluorinated reagent was successfully deployed for labeling three radiopharmaceuticals, [¹⁸F]FDG, [¹⁸F]AV-45 and [¹⁸F]FMISO. Particularly, [¹⁸F]AV-45, a PET imaging agent targeting amyloid-plaques in the brain, was successfully implemented on an automated synthesis module (BIBD-F). Since the method trapped [K2.2.2K][¹⁸F]F in wet/acetonitrile avoiding the azeotropic drying step, this process could be further developed as an alternative method for routine preparation of many other ¹⁸F radiopharmaceuticals.