New aspects on the preparation of [11C]Methionine—a simple and fast online approach without preparative HPLC

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Abstract

At present, most data available on PET imaging of brain tumors using amino acids are based on l-[S-methyl-11C]methionine (MET). This radiopharmaceutical accurately delineates tumor extent, sometimes even better than CT. Since MET is playing such an important role for PET, a potent preparation method for this radiotracer allowing frequent syntheses for PET routine is desirable. Therefore, a simple disposable synthesis module was conceived without HPLC purification. Using a solid supported [11C]methylation on Al2O3 leads to the simplification of the preparation requiring only filtration for separation of precursor and MET. The presented method is able to produce high purity MET in excellent yields enough to serve several consecutive patients.

Introduction

2-[18F]Fluoro-2-deoxy-d-glucose (FDG) and l-[S-methyl-11C]methionine (MET) are widely used tracers for oncological PET studies. MET has the potential to image the increased dependency of malignant tumors on methionine, although the exact mechanisms of MET uptake in cancer cells are still not fully understood (Nakada, 2004). MET was found to be more accurate in imaging the extent of a brain tumor than FDG and the conventional computed tomography (CT) scan (Becherer et al., 2003). The major shortcoming of MET is the 20-min half-life of 11C. Since the limiting factor for good preparation yields was our online [11C]methyl iodide module, only a potent and powerful radiosynthesis method of MET would allow for our routine demands of at least 3 consecutive patients. Various methods have been presented in the literature ranging from organometallic precursors (Bolster et al., 1986)—yielding in a racemate mixture—over a l-homocysteine thiolactone precursor (Comar et al., 1976; Mizuno et al., 1993) to l-S-benzyl homocysteine (Långström and Lundqvist, 1976). The latter methods produce pure L-MET without further chiral purification but still demand a time consuming semi-preparative high performance liquid chromatography (HPLC) purification. Pascali et al presented a method starting with an l-homocysteine thiolactone precursor and the purification with just C18 SepPak cartridges (Pascali et al., 1999). An alternative method was presented by Schmitz et al (1995): a solid phase supported regioselective synthesis of L-MET without requiring any HPLC purification. Therefore the aim of the presented study was the evaluation, implementation and improvement of this method presented by Schmitz et al. (1995) for our demands with a remotely controlled apparatus using disposable tubing and containers.

Section snippets

General

l-homocysteine was obtained from ABX (Radeberg, Germany), acetonitrile, potassium dihydrogen phosphate, ninhydrin and phosphoric acid were purchased from Merck (Darmstadt, Germany). Ethanol (100%, Ph.Eu.) was purchased from Riedel-de Haën (Seelze, Germany), physiological saline was obtained from the general hospital pharmacy (AKH Wien, Austria). Al2O3/KF (Nr 60244) was obtained from Sigma Aldrich Chemical company (Steinheim, D). All reagents were of the highest purity available and used without

Results

Average absolute yields from 258 syntheses were 10.22±4.42 GBq (arithmetic mean±SD) starting from 47.59±5.56 GBq [11C]COx at end of bombardement representing 21.22±7.9%, not corrected for decay. Starting activities from the cyclotron always ranged from 40.1 to 63.5 GBq and MET yields ranged from 5.1 to 23.4 GBq. 6 failure syntheses were observed (2.3%, 4 technical problems at the [11C]methyl iodide module, 2 operator mistakes).

The analytical HPLC-method showed retention times of 2.3 min for ethanol,

Discussion

The preparation of MET for routine PET has already been presented in 1976 (Comar et al., 1976). In recent years, there is common sense, that MET and other amino acids are used as a marker for viable brain tumor tissue and are more sensitive and specific than FDG in PET. They are superior in detecting brain tumor recurrences. At present, most data available on PET imaging of brain tumors using amino acids are based on MET. This radiopharmaceutical accurately delineates tumor extent, sometimes

Conclusion

The presented method is fast and feasible and allows for the sequential online preparation of MET for routine PET. The module is made up of disposable components and standard valves and thus the requirements for cleaning are minimized. The easy and remotely controlled handling leads to a minimum of failed syntheses. The presented method is able to produce high quality MET in excellent yields—sufficient to serve several consecutive routine PET patients.

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