Methods for the incorporation of carbon-11 to generate radiopharmaceuticals for PET imaging.

Radiopharmaceuticals can range from the small and simple (e.g. small molecules, sugars, peptides, amino acids) to the large and complex (e.g. taxol, large peptides, proteins, antibodies) and can be custom-synthesized for applications in, for example, neurology, oncology, and cardiology. Radiochemistry is the process by which such molecules are tagged with a radioisotope. Owing to the high levels of radiation involved, it is frequently not a trivial process. In the last two or three decades, a broad range of ingenious radiochemical reactions and automated hardware solutions have been developed to simplify the process. A detailed discussion of these developments is beyond the scope of this Highlight; however, the subject has received much attention in recent review articles in the main-stream organic chemistry literature, most noticeably in a comprehensive article by Miller et al. The scope of PET imaging is perhaps endless, especially when one considers how many biochemical processes are occurring in the human body (or elsewhere in nature) at any given time. Therefore, future applications in, for example, genomics and stem-cell research are expected and eagerly anticipated. Despite this potential, and echoing the opinion of Miller et al. , PET imaging is currently underexploited because of the limited availability of pertinent radiopharmaceuticals. Access to radiopharmaceuticals is in turn restricted by the arsenal of labeling reactions at the radiochemist s disposal. This problem is exacerbated by the fairly small number of radiochemists developing new reactions. The slow process of reaction development is often hindered further when forced into second place behind increasing clinicalproduction demands. However, the growing numbers of traditional organic chemists entering the radiochemistry arena worldwide, a trend reflected by the recent flurry of review articles, offers a promising solution to these problems. Many innovative organic chemistry techniques (e.g. solid-phase synthesis, fluorous technology, microfluidics) and reactions (e.g. the Huisgen cycloaddition (click chemistry), palladium-catalyzed cross-coupling reactions) are beginning to be adapted for radiochemical synthesis. Carbon-11 is one of the most useful radioisotopes to work with owing to the ease with which it can be incorporated into many molecules without a significant effect on biological activity (in contrast to the detrimental effect on activity frequently encountered upon the addition of an [F]fluoroethyl group to a promising pharmacological scaffold). At the same time, however, competing side reactions with environmental carbon-12 sources (e.g. atmospheric CO2) and the 20 min half-life make high-specific-activity radiopharmaceuticals labeled with carbon-11 some of the most synthetically challenging to prepare. The radiochemical reactions have to be very fast (must typically occur within 5 min), high yielding, and clean enough that crude reaction mixtures can be purified rapidly (by semipreparative HPLC or solid-phase extraction (SPE) techniques) to provide pure radiopharmaceuticals as sterile, pyrogen-free isotonic solutions suitable for intravenous injection. Carbon-11 is generated in the cyclotron target by a nuclear reaction with nitrogen-14 [Eq. (1)]. The resulting Figure 1. PET imaging: from bench to bedside.