Radiolysis of 2-[18F]fluoro-2-deoxy-d-glucose (FDG) and the role of reductant stabilisers
Introduction
2-[18F]Fluoro-2-deoxy-d-glucose (FDG) is the most universally used radioactive drug (radiopharmaceutical) in the rapidly expanding medical imaging technology of Positron Emission Tomography (PET). In 2004, there were 531 new scanners sold worldwide for PET imaging procedures, rising to 608 new scanners in 2005—a 15% increase. In 2004, approximately 1 million PET procedures were performed raising to 1.2 million in 2005—a 24% increase and expected to rise to 4.4 million patient scans annually by 2012 (Society of Nuclear Medicine News Release June 2006). The vast majority of these PET patient scans utilise FDG as the radiopharmaceutical of choice and the projected growth in PET services is expected to create a 30% annual increase in FDG demand for several years to come. FDG supply is currently met from compact medical cyclotron installations where, over the past decade, the scale of FDG manufacture has expanded 20-fold or more (from ∼10 GBq per batch to more than 200 GBq per batch). The expected expansion of PET services in the near future is likely to further stimulate FDG manufacture on an even larger scale that may result in new stability challenges for the radiopharmaceutical chemist.
In addition to radioactive decay, FDG decomposes in vitro resulting in the degradation of the radiochemical purity of this radiopharmaceutical with time. The build up of the concentration of free [18F]fluoride is the most prominent consequence of decomposition. The various national pharmacopoeias stipulate the minimum purity that a drug product must meet at the time of administration to humans (typically for FDG, >95% of [18F] radioactivity must be as FDG, British Pharmacopoeia (BP) 2005) and these purity limits generally determine the shelf life for unstable drug products. Freshly synthesised FDG usually has an initial radiochemical purity of >99% that may decline to <90% in a few hours depending upon the storage conditions and the rate of decomposition and this has been explored by several investigators. Wagner (2003) investigated the stability of FDG during steam autoclaving for 5 min at 134 °C at pH 5.5 and detected up to 8% epimerisation of the fluorodeoxyglucose into fluorodeoxymannose (FDM) but without defluorination release of [18F]fluoride into solution. Karwath et al. (2005) examined the stability of FDG solutions as a function of pH at elevated temperature and time. When FDG was autoclaved at 135 °C for 3.5 min, the radiochemical purity of the FDG decreased from ∼100% to less than 50% as the pH increased from 5.0 to 8.0. A concomitant build-up of the impurities from epimerisation (FDM) and hydrolysis ([18F]fluoride) was also observed as the pH tended to alkaline conditions. At ambient temperature, Karwath also reported a small decline in FDG radiochemical purity as a function of time, pH and radioactive concentration with a maximum purity loss of 3.3% over 10 h at pH 7.2 for solutions with a maximum radioactive concentration of 2.8 GBq/mL. Jimenez et al. (2006) also observed an increase in the [18F]fluoride concentration of FDG solutions over 5 h storage at ambient temperature that could be minimised by dilution of the FDG solution with physiological saline. The usual method for FDG synthesis (Hamacher et al., 1986) employs nucleophilic substitution of fluoride into tetra-acetyl mannose triflate and provides FDG contained in ∼5 mM glucose solution. Buriova et al. (2005) examined FDG solutions (0.4–1.6 GBq/mL) after decay and besides free fluoride, found the main autoradiolysis products were oxidation products of glucose (arabinose and gluconic acid) in the μM concentration range. Using tracer amounts of [18F] activity (∼40 MBq), Osborn et al. (2005) studied the chemistry of FDG synthesis in detail but did not follow the subsequent decomposition. Kruijer and Knight (2003) monitored the decomposition of dilute FDG solutions (111 MBq/mL) during steam autoclaving (134 °C for 5 min) and reported the value of weak organic acids and acidic pH for improving the stability of FDG at elevated temperatures. For large-scale manufacture, radiolytic decomposition at room temperature can become problematic. Kiselev and Tadino (2002) studied the stability of FDG in production scale batches (82–106 GBq/9 mL) and reported that a minimum ethanol concentration of 0.1% was necessary to maintain the radiochemical purity of FDG above 90% for the 14 h shelf life of the product.
These publications indicate that FDG is a radiopharmaceutical that is unstable at elevated temperatures, alkaline pH and in highly radioactive concentrations and has prompted an examination of the stability of FDG synthesised at this institution. Additional factors influencing the stability of FDG, including the absorbed dose, radiolysis of the solvent and the presence of reductants were investigated.
Section snippets
Experimental
Routine FDG synthesis is performed daily for clinical PET scanning using a GE PET trace cyclotron, automated chemistry synthesisers and quality tested for compliance with the BP 2005 specifications.
Results and discussion
Fig. 2 shows the results of a pH 5.5 room temperature stability study on the samples taken at the end of synthesis, for two similar batches of FDG where the initial radioactive concentrations were 11.5 GBq/mL (upper trace) and 6.3 GBq/mL (lower trace). The [18F]fluoride concentration remained below the 5% BP 2005 limit for the 14 h shelf life for the 6.3 GBq/mL solution but reached the limit after only 4 h for the more concentrated solution.
Ethanol stabiliser at a minimum concentration of 0.1% was
Conclusion
Calculation of the absorbed dose in the bulk radioactive solution allows an estimate to be made of the amount of radiolytically produced hydrogen peroxide. The concentration of hydrogen peroxide generated in situ in decayed FDG solutions is dependent upon the absorbed dose and the radioactive concentration and is one of the factors affecting the stability of FDG solutions. The stability of FDG and the shelf life of this radiopharmaceutical can be manipulated by altering the radioactive
Acknowledgements
The author gratefully acknowledges the assistance of Dr. D. Henderson and Dr. S. Eberl for valuable discussions and for the supply of FDG samples and Ms. J. Towson for dosimetry information.
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