Radiotracer synthesis from [11C]-iodomethane: a remarkably simple captive solvent method

doi:10.1016/S0969-8051(00)00132-3

Nuclear Medicine and Biology

Volume 27, Issue 6, June 2000, Pages 529-532

https://doi.org/10.1016/S0969-8051(00)00132-3 Get rights and content

Abstract

A new method of [¹¹C]-methylation is described, which attains the goals of simplicity, high radiochemical yields, speed, versatility, and automation. A standard high performance liquid chromatography (HPLC) injection loop on a standard HPLC injection valve is loaded with a solution (80 μL) of precursor (0.3–1.0 mg) in dimethyl formamide (DMF) or dimethyl sulfoxide (DMSO) (+ base if required). At ambient temperature [¹¹C]-iodomethane is passed through the loop for 3–4 min with >90% trapping of activity. After a further 1–5 min, the contents of the loop are quantitatively injected onto the HPLC column for purification. Radiochemical yields are equal to or superior to conventional solution methods in all cases, even though no heat is applied. [¹¹C]-labeled radiotracers that have been prepared by this method for human or animal studies include Raclopride, N-methylspiperone, Ro 15-1788, FLB 457, RTI-32, Rolipram, SCH 23390, and SKF 82957. Since no vials, transfer lines, cooling, heating, or sealing valves are required, no transfer losses occur, yields are high, and cleanup is minimal, this “loop method” is ideal for most radiopharmaceuticals prepared from [¹¹C]-iodomethane.

Introduction

Methylation of suitable precursors with [¹¹C]-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 [¹¹C]-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 simplify and automate the [¹¹C]-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 [¹¹C]-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 [¹¹C]-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, and especially the last, have 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 and 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 in 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 and some require nonproprietary 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. We report here a new method that attains the goals of simplicity, high radiochemical yields, speed, versatility, and ease of automation. Without using any additional solid support and with no heating or cooling, [¹¹C]-iodomethane is trapped directly in a standard HPLC loop coated with precursor solution, reacted, and directly injected onto the HPLC purification column.

Section snippets

Methods

Precursors (normethyl) for [¹¹C]-methylation were synthesized in house (RTI-32, rolipram, FLB 457, DASB) or commercially available (SCH 23390, NMS, SKF 82957). Raclopride precursor was a gift from Astra Arcus AB (Sodertalje, Sweden) and Ro 15-1788 precursor was a gift from Hoffman-LaRoche (NJ, USA).

Results and discussion

The “loop method” described above, which consists of trapping and reacting [¹¹C]-iodomethane directly in the injection loop of the HPLC valve, has been applied to the synthesis of a variety of PET radiopharmaceuticals (Table 1). In all cases the method was successful, with results equal to or superior those using conventional solutions in a vial method. This includes parameters of success such as trapping of [¹¹C]-iodomethane, radiochemical yield, time of synthesis, purity of final product, and

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Technical noteRadiotracer synthesis from [11C]-iodomethane: a remarkably simple captive solvent method

Abstract

Introduction

Section snippets

Methods

Results and discussion

Appl. Radiat. Isot. Int. J. Appl. Instrum. Part A

Appl. Radiat. Isot.

Int. J. Appl. Radiat. Isot.

Appl. Radiat. Isot.

Appl. Radiat. Isot.

Appl. Radiat. Isot.

Nucl. Med. Biol.

Appl. Radiat. Isot.

Nucl. Med. Biol.

Technical note
Radiotracer synthesis from [¹¹C]-iodomethane: a remarkably simple captive solvent method