Ding Y S, Fowler J S, Gatley S J, Dewey S L, Wolf A P
Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973.
J Med Chem. 1991 Feb;34(2):767-71. doi: 10.1021/jm00106a043.
The first example of a no-carrier-added 18F-labeled catecholamine, 6-[18F]fluoronorepinephrine (6-[18F]FNE), has been synthesized via nucleophilic aromatic substitution. The racemic mixture was resolved on a chiral HPLC column to obtain pure samples of (-)-6-[18F]FNE and (+)6-[18F]FNE. Radiochemical yields of 20% at the end of bombardment (EOB) for the racemic mixture (synthesis time 93 min), 6% for each enantiomer (synthesis time 128 min) with a specific activity of 2-5 Ci/mumol at EOB were obtained. Chiral HPLC peak assignment for the resolved enantiomers was achieved by using two independent methods: polarimetric determination and reaction with dopamine beta-hydroxylase. Positron emission tomography (PET) studies with racemic 6-[18F]FNE show high uptake and retention in the baboon heart. This work demonstrates that nucleophilic aromatic substitution by [18F]fluoride ion is applicable to systems having electron-rich aromatic rings, leading to high specific activity radiopharmaceuticals. Furthermore, the suitably protected dihydroxynitrobenzaldehyde 1 may serve as a useful synthetic precursor for the radiosynthesis of other complex 18F-labeled radiotracers.
首例无载体添加的18F标记儿茶酚胺——6-[18F]氟去甲肾上腺素（6-[18F]FNE），已通过亲核芳香取代反应合成。外消旋混合物在手性高效液相色谱柱上拆分，以获得(-)-6-[18F]FNE和(+)-6-[18F]FNE的纯样品。外消旋混合物在轰击结束时（EOB）的放射化学产率为20%（合成时间93分钟），每种对映体的产率为6%（合成时间128分钟），EOB时的比活度为2 - 5 Ci/μmol。通过两种独立方法实现了拆分后对映体的手性高效液相色谱峰归属：旋光测定和与多巴胺β-羟化酶反应。用外消旋6-[18F]FNE进行的正电子发射断层扫描（PET）研究表明，狒狒心脏对其摄取和保留率很高。这项工作表明，[18F]氟离子的亲核芳香取代反应适用于具有富电子芳香环的体系，可得到高比活度的放射性药物。此外，适当保护的二羟基硝基苯甲醛1可作为合成其他复杂的18F标记放射性示踪剂的有用前体。
