Abstract
BackgroundCurrent automated radiosynthesizers are generally optimized for producing large batches of PET tracers. Preclinical imaging studies, however, often require only a small portion of a regular batch, which cannot be economically produced on a conventional synthesizer. Alternative approaches are desired to produce small to moderate batches to reduce cost and the amount of reagents and radioisotope needed to produce PET tracers with high molar activity. In this work we describe the first reported microvolume method for production of [18F]Florbetaben for use in imaging of Alzheimer’s disease.ProceduresThe microscale synthesis of [18F]Florbetaben was adapted from conventional-scale synthesis methods. Aqueous [18F]fluoride was azeotropically dried with K2CO3/K222 (275/383 nmol) complex prior to radiofluorination of the Boc-protected precursor (80 nmol) in 10 μL DMSO at 130 °C for 5 min. The resulting intermediate was deprotected with HCl at 90 °C for 3 min and recovered from the chip in aqueous acetonitrile solution. The crude product was purified via analytical scale HPLC and the collected fraction reformulated via solid-phase extraction using a miniature C18 cartridge.ResultsStarting with 270 ± 100 MBq (n = 3) of [18F]Fluoride, the method affords formulated product with 49 ± 3% (decay-corrected) yield,> 98% radiochemical purity and a molar activity of 338 ± 55 GBq/μmol. The miniature C18 cartridge enables efficient elution with only 150 μL of ethanol which is diluted to a final volume of 1.0 mL, thus providing a sufficient concentration for in vivo imaging. The whole procedure can be completed in 55 min.ConclusionsThis work describes an efficient and reliable procedure to produce [18F]Florbetaben in quantities sufficient for large-scale preclinical applications. This method provides very high yields and molar activities compared to reported literature methods. This method can be applied to higher starting activities with special consideration given to automation and radiolysis prevention.
Highlights
Current automated radiosynthesizers are generally optimized for producing large batches of Positron emission tomography (PET) tracers
A number of tracers were developed to target amyloid-beta (Aβ) plaques which are correlated with the progression of Alzheimer’s disease (Hardy and Selkoe 2002), and it is believed that the high sensitivity and specificity of PET can aid in early diagnosis of dementia and its grading (Ossenkoppele et al 2015)
Fluorination efficiency increased as temperature was increased from 90 to 130 °C, and while there was a very slight reduction in collection efficiency over this temperature range, the overall Radiochemical yield (RCY) of the intermediate increased with increasing temperature (Fig. 3a)
Summary
Current automated radiosynthesizers are generally optimized for producing large batches of PET tracers. In this work we describe the first reported microvolume method for production of [18F]Florbetaben for use in imaging of Alzheimer’s disease. A number of tracers were developed to target amyloid-beta (Aβ) plaques which are correlated with the progression of Alzheimer’s disease (Hardy and Selkoe 2002), and it is believed that the high sensitivity and specificity of PET can aid in early diagnosis of dementia and its grading (Ossenkoppele et al 2015). The tracers are used for accurate dementia grading and early detection in at-risk populations In research, these tracers are useful for testing of new treatments and understanding their influence on disease progression (Brendel et al 2016; Brendel et al 2018; Sabri et al 2015; Blume et al 2018; Rominger et al 2013; Sacher et al 2019). There seem to be mixed reports about the importance of molar activity in small animal amyloid imaging (Snellman et al 2014), but it has been reported that detection of relatively immature (small and diffuse) amyloid lesions in mouse brain (with [11C]PIB) is especially sensitive to molar activity (Maeda et al 2007)
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