Method for the synthesis of radiolabeled compounds

Details Method for the synthesis of radiolabeled compounds Method for the synthesis of radiolabeled compounds

2002-01-31

2004-06-15

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

C424S001650, C424S001810, C424S001850, C424S001890

Reexamination Certificate

active

06749830

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a method for radiolabeling chemical compounds. Specifically, the method of the invention provides a simple and efficient method to [
11
C]-methylate target substrates.
BACKGROUND OF THE INVENTION
Methylation of suitable precursors with [
11
C]-iodomethane continues to be the workhorse method of synthesis of a majority of positron emission tomography (PET) radiotracers, especially in the area of receptor imaging. Many improvements have been made in the production of [
11
C]-iodomethane, most recently with the introduction of “gas-phase methods” which are highly automated and produce a product with very high specific activity (1,9,10). Efforts to simply and automate the [
11
C]-methylation reaction and purification have been less spectacular. Many attempts to streamline the process have revolved around the idea of eliminating the traditional “solution in reaction vial” whereby [
11
C]-iodomethane is distilled into a vessel containing solvent, precursor, and base/catalyst if required (1,8,11). In this common scenario, cooling of the vessel for trapping [
11
C]-iodomethane is usually required followed by sealing of the vessel, heating to effect reaction, quenching of the reaction, and transferring of the vessel contents to a high performance liquid chromatography (HPLC) system for purification. The streamlining and automation of this sequence of events, especially the last, has proven onerous.
An attractive technique to surmount some of these problems was described in the pioneering papers of Jewett and Watkins on captive solvent chemistry (4,6,17). Their goal was to develop a solid support to trap reagents and iodomethane together, eliminating the need for a reaction vessel with its septa, needles, and their associated problems. Similar efforts have been forthcoming from other groups where the technique has been named on-line, solid-phase, or immobilized techniques (3,14,16,19). When the solid support is plumbed in to take the place of the HPLC sample loading loop then transfer losses from reaction vessel to loop can also be eliminated and the process simplified.
Such captive solvent techniques have not been widely adopted by the field, perhaps because no one method fulfills all the requirements of ease of use reproducibility, and versatility. Some methods have not been fully integrated as part of the HPLC system (17,19), some require non-proprietary solid-supports (6,14), while others can degrade the HPLC purification of the radiotracer (3). In addition, cooling and heating the reaction site are still necessary steps in the synthetic sequence.
There remains a need for a simple, fast and versatile method to radiolabel chemical compounds, specifically via [
11
C]-methylation reactions, which provides high radiochemical yields and is easily automated.
SUMMARY OF THE INVENTION
A new method to radiolabel chemical compounds has been developed. Specifically the method involves the [
11
C]-methylation of chemical compounds. In general terms, the method involves trapping a radiolabeling reagent directly in a standard HPLC loop coated with precursor solution, allowing the reagents to react, and then directly injecting the reaction mixture onto an HPLC purification column. The method does not require the use of any additional solid support nor any heating or cooling.
The present invention therefore provides a method for radiolabeling precursor chemical compounds comprising the steps of:
injecting a sample comprising a precursor chemical compound into an injection loop of a high performance liquid chromatograph (HPLC);
injecting a radiolabeling reagent into the injection loop;
allowing the radiolabeling reagent to react with the precursor chemical compound, to provide a reaction mixture comprising a radiolabeled compound;
injecting the reaction mixture into the HPLC column; and
isolating the radiolabeled compound.
In embodiments of the present invention, the radiolabeling reagent is a [
11
C]-methylating reagent. Accordingly, the present invention further provides a method for [
11
C]-methylation of precursor chemical compounds comprising the steps of:
injecting a sample comprising a precursor chemical compound into an injection loop of a high performance liquid chromatograph (HPLC);
passing [
11
C]-iodomethane through the injection;
allowing the [
11
C]-iodomethane to react with the precursor chemical compound, to provide a reaction mixture comprising a [
11
C]-methylated compound;
injecting the reaction mixture into the HPLC column; and
isolating the [
11
C]-methylated compound.
Some literature methods for performing [
11
C]-methylation reactions involve the use of a solid support as the means to bring together precursor and [
11
C]-iodomethane. A disadvantage of this is that the reaction mixture is strongly retained by the support with the result that HPLC separations are less efficient (3). Using only the loop as a support avoids this pitfall and no differences in chromatographic separations could be discerned as compared to injections of solutions of reaction mixtures.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.


REFERENCES:
Crouzel, C. Längström, B., Pike, V.W., and Coenen, H.H. (1987) Recommendations for a practical production of [11C]methyl iodideAppl. Radiat. Isot. Int. J. Appl. Instrum. Part A38, 601-603.
Dannals, R.F., Ravert, H.T., and Wilson, A.A. (1990) Radiochemistry of Tracers for Neurotransmitter Receptor Studies. In:Quantitative Imaging: Neuroreceptors, Neurotransmitters, and Enzymes. (Edited by Frost, J.J. Wagner Jr., H.N. pp. 19-35,. Raven Press, New York.
Iwata. R., Pascali, D., Yuasa, M., Yanai, K., Takahashi, T., and Ido, T. (1992) On-line [11C]Methylation using [11C]Methyl Iodide for the Automated Preparation of11C-RadopharmaceuticalsAppl. Radiat. Isot. 43, 1083-1088.
Jewett, D., Ehrenkaufer, R., and Ram, S. (1985) A Captive Solvent Method for Rapid Radiosynthesis: Application to the Synthesis of [1-11C]Palmitic AcidInt. J. Appl. Radiat. Isot. 36,672-674.
Jewett, D.M. (1992) A Simple Synthesis of [11C]Methyl TriflateAppl. Radiat. Isot. 43, 1383-1385.
Jewett, D.M., Manger, T.J., and Watkins, G.L. (1991) Captive Solvent Methods for Fast Simple Carbon-11 Radioalkylations. In:New Trends in Radiopharmaceutical Synthesis, Quality Assurance and Regulatory Control(Edited by Emran, A.M.) pp. 387-391. Plenum Press, New York.
Langer, O., Nagren, K., Dolle, F., Lundkvist, C., Sandell, J., Swahn, C.-G., Vaufrey, F., Crouzel, C., Maziere, B., and Halldin, C. (1999) Precursor Synthesis and Radiolabeling of the Dopamine D2 Receptor Ligand . [11C]Raclopride from [11C]Methyl Triflate.J. Labelled Compd. Radiopharm. 42, 1183-1193.
Längström, B., and Lundqvist. H. (1976) The preparation of11C-methyl iodide and its use in the synthesis of11C-methyl-L-methionineAppl. Radiat. Isot. 27, 357-363.
Larsen, P., Ulin, J. Dahlstrom, K., and Jensen, M. (1997) Synthesis of [11C]Iodomethane by Iodination of [11C]MethaneAppl. Radiat. Isot. 48,53-157.
Link, J.M., Krohn, K.A., and Clark, J.C. (1997) Production of [11C]CH3I by single pass reation of [11C]CH4with I2Nucl Med Biol24, 93-97.
Marazano, C., Maziere, M., Berger, G., and Comar, D. (1977) Synthesis of methyl iodide-11C and formaldehyde-11CAppl. Radiat. Isot. 28, 49-52.
Maziere, B., Coenen, H., Halldin, C., Nagren, K., and Pike, V. (1992) PET radioligands for dopamine receptors and re-uptake sites: chemistry and bioch

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