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Abstract  

For the radiofluorination of benzenes and benzene derivatives, the electrophilic reaction with [18F]F2 is a very common route. Yet, aromatic nucleophilic substitution (SNAr) by n.c.a [18F]fluoride, which can be produced efficiently in high amounts, has been considered to be very desirable. However, to facilitate 18F-labelling via SNAr at an electron rich aromatic system, an appropriate leaving group must be present together with an auxiliary group in ortho or para position to the leaving group. An interesting alternative for the auxiliary group is the heteroatom of a heteroaromatic system, for which pyridine is a leading example. Dolci et al. (J Label Compd Radiopharm 42:975–985, <cite>1999</cite>) have evaluated the scope of the nucleophilic aromatic fluorination of 2-substituted pyridine rings using the activated K [18F]F-K222 complex. As methyl and methoxy groups are known to enhance the electron density of an aromatic system by the +I and the +M effect, respectively, SNAr is unlikely to occur. Until now, the effect of these substituents has not been studied towards the 18F-radiofluorination of substituted 2-nitropyridines by use of [18F]fluoride. Therefore, we have investigated the effect of methoxy and methyl groups in 2-nitropyridines. The results showed that 3-methoxy-2-nitropyridine and 3-methyl-2-nitropyridine can efficiently be substituted by [18F]fluoride with high RCY’s (70–89%) in short reaction times (1–30 min) at a reaction temperature of 140 °C. Moreover, 3-methoxy-6-methyl-2-[18F]fluoropyridine was obtained from the corresponding nitro-precursor in a high yield of 81 ± 1% after 30 min at 140 °C. In case of 2-nitropyridines data indicates the effect of methyl and methoxy groups on SNAr to be of minor importance.

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Abstract  

In homoaromatic systems, isotopic exchange (18F/19F) was previously (J Label Compd Radiopharm 18(12):1721–1730 [<cite>2</cite>], J Chem Soc Perkin Trans 1(3):295–298 [<cite>3</cite>]) proven to be advantageous, yet in general specific activity is thought to be low. For heteroaromatic systems, in particular, very few examples are published regarding the 18F-labelling of 2-substituted pyridines (J Label Compd Radiopharm 42:975–985 [<cite>9</cite>]). Therefore, in 2-fluoropyridines, we decided to study the 18F labelling by isotopic exchange (18F/19F). The radiochemical yield for 2-fluoropyridine was 90 ± 2%. Even if 2-fluoropyridine was substituted by an electron-donating group such as a methyl or a methoxy group, radiochemical yields were 80 ± 1 and 78 ± 1%, respectively. Although in benzenes, these substituents are known to decrease nucleophilic substitutions by 18F-Fluoride significantly. Moreover, by choosing appropriate concentrations of 2-fluoropyridines, reasonably high specific activities up to 10 GBq/μmol were obtained.

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Abstract  

In this work, we tested the applicability of several methyl substituted benzyl groups as an alternative to the methyl group for the protection of the hydroxyl groups in the nucleophilic aromatic radiofluorination. As a model synthesis, the no-carrier-added (n.c.a.) preparation of 2-[18F]fluoro-3-hydroxy-6-methylpyridine from O-protected 3-hydroxy-6-methyl-2-nitropyridine was chosen. Conditions for acidolytic and hydrogenolytic cleavage of heteroaryl esters were studied. Among various protecting groups tested, 4-methylbenzyl and 2,4-dimethylbenzyl groups proved to be the best by resulting in about 70% yields of [18F]-labelled product after hydrolysis with 32% HCl at 120 °C for 10 min. Furthermore, 4-methylbenzyl ester cleaved readily under catalytic transfer hydrogenation condition using ammonium formate and 10% Pd/C in boiling methanol to give 2-[18F]fluoro-3-hydroxy-6-methylpyridine in radiochemical yield of 75% within a reaction time of 10 min. Conditions for the cleavage of both 4-methylbenzyl and 2,4-dimethylbenzyl esters are well suited for the implementation into an automated synthesis module.

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Abstract  

The synthesis of the three 18F-labeled 2-nitroimidazoyl oximes is described to be used as possible hypoxia tumor imaging agents. The title oximes were successfully synthesized in a four step sequence, characterized, and finally radiolabeled. Under optimized labeling conditions, the radiochemical yields of the three markers were in the range of 69–80%.

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Journal of Radioanalytical and Nuclear Chemistry
Authors:
Noeen Malik
,
Xian Lin
,
Dirk Löffler
,
Bin Shen
,
Christoph Solbach
,
Gerald Reischl
,
Wolfgang Voelter
, and
Hans-Jürgen Machulla

Abstract  

For detection of hypoxic tumor tissue, all radiotracers synthesized until now, are based on the concept that cellular uptake is being controlled by diffusion. As a new approach, we chose the concept to have the tracer hypothetically transported into the cells by well known carrier systems like the amino acid transporters. For this purpose, radiosynthesis of O-[2-[18F]fluoro-3-(2-nitro-1H-imidazole-1yl)propyl]tyrosine ([18F]FNT]) was carried out from methyl 2-(benzyloxycarbonyl)-3-(4-3-(2-nitro-1H-imidazol-1-yl)-2-(tosyloxy)propoxy) phenyl)propanoate via no-carrier-added nucleophilic aliphatic substitution. After labelling, 81 ± 0.9% of labelled intermediate i.e. methyl 2-(benzyloxycarbonyl)-3-(4-(2-[18F]fluoro-3-(2-nitro-1H-imidazole-1-yl)propoxy) phenyl)propanoate was obtained at 140 °C. At the end of radiosynthesis, [18F]FNT was obtained in an overall radiochemical yield of 40 ± 0.9% (not decay corrected) within 90 min in a radiochemical purity of >98% in a formulation ready for application in the clinical studies for PET imaging of hypoxia.

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