Synthesis of PET radiopharmaceuticals

General Considerations The synthesis of PET radiopharmaceuticals has several peculiarities substantially different from the procedures followed to prepare conventional y-emitting radiopharmaceuticals. A very important issue that must be considered is the specific activity. For all radiopharmaceuticals it is usually very high and can be calculated from the formula... 

The synthesis of PET radiopharmaceuticals is always carried out at very small scale (only a few dozen micrograms of the radiopharmaceutical are obtained) and each batch can sometimes only be used for a single patient or a few patients at most. Consequently, there is always a big excess of the precursor in the reaction medium, and proper purification systems must be used to get rid of all the possible contaminants. Such systems must also be very efficient and fast, and the most usual is to apply either semipreparative high-performance liquid chromatography (HPLC) or solid-phase extraction-based procedures. 

The position of the radionuclide in the molecule of interest is also critical as it will affect the biological behavior of the radiopharmaceutical. Chemical reactions must be designed to be stereospecific in many cases, as the production of a mixture of different stereoisomers complicates the purification of the final radiopharmaceutical. Synthesis procedures must also be easy to automate, as very elevated activities are used for the synthesis of PET radiopharmaceuticals (several curies usually) and appropriate radiation protection systems must be used. 

Synthesis of PET Radiopharmaceuticals Albeit the requirements for the synthesis of PET radiopharmaceuticals previously described, the synthesis process could conceptually be reduced to a very simple scheme, as shown in Figure 6. 

Conventional manual methods of synthesis of radiopharmaceuticals using a high level of radioactivity are likely to subject the persons involved in the synthesis to high radiation exposure. This is particularly true with short-lived positron emitters such as UC, 13N, 150, and 18F, because the quantity of these radionuclides handled in the synthesis is very high. To minimize the level of exposure, automated modules have been devised for the synthesis of PET radiopharmaceuticals. 

In larger departments facilities for the synthesis of PET radiopharmaceuticals are available for which a local cyclotron may be needed. The use of PET tracers may have advantages in terms of speed, image resolution and radiation burden. Reasons for installing a local cyclotron are the extent of PET diagnostics and research, the demand for very short-lived PET radiopharmaceuticals (e.g. based on and and the lack of EDG availability from commercial suppliers. 

In 2003 LJngstrOm and Samuelsson described the synthesis of a radiopharmaceutical for PET (positron emission tomography) using a microwave-assisted Stille reaction [25]. l-(2 -Deoxy-2 -fluoro- 6-D-arabinofuranosyl)-... 

Alexoff, D. L. Automation for the synthesis and apphcation of PET radiopharmaceuticals, BNL-68614 Officinal File Copy... 

Many radiopharmaceuticals for PET are labelled with 18F. 18F decays with emission of a positron with a relative low energy which limits its range in the body and thus enhances the resolution of a PET study. A second advantage of 18F is the half-life of 110 minutes which allows synthesis and PET studies, and allows use in humans, not causing radiation damage. 

Because of the unique operational and safety requirements of radiopharmaceutical synthesis, the motivation for the development of automated systems is clear. These unique constraints include short synthesis times and control from behind bulky shielding structures that make both access to and visibility of radiochemical processes and equipment difficult. The need for automated systems is particularly expressed for PET radiopharmaceutical synthesis, with the short-lived radionuclides emitting high-energy y photons at 511 keV. Automated synthesis systems require no direct human participation. The short half-lives of the PET radionuclides may require repeated synthesis during the day, thus being a potential radiation burden for the operator when not using automated systems. 

For PET radiopharmaceuticals we must always consider that synthesis processes must be extremely fast. Consequently, synthesis schemes with as few steps as possible must be used, and each of the steps must proceed with high efficiency. The incorporation of the radionuclide to the molecule should ideally be done in the final steps of the synthesis. In this way two objectives can be achieved reduce the overall synthesis time (thus increasing the yield) and reduce the number of side reactions and secondary undesired products obtained during the synthesis. 

The half-life of 18F (109 min) is sufficiently long to carry out complex synthesis procedures, apply long PET imaging protocols, and carry out metabohte analysis. Furthermore, it is possible to produce the radiopharmaceutical in a laboratory and transport it to a distant site only equipped with an imaging device. These kinds of satellite PET centers have boomed all around the world and permitted the fast expansion of PET as an everyday clinical tool in certain pathologies (mainly in oncological diseases). 

FIGURE 7 Automated synthesis module for PET radiopharmaceutical synthesis located in a shielded hot cell. (Photo courtesy of PET-CUN Center, University of Navarra.)... 

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