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A successful positron emission tomography imaging program involving carbon-11 radiotracers demands fast, efficient, and reliable synthesis methods, requiring an on-site cyclotron and radiochemistry group, as well as clinical staff trained to operate under the unique constraints of the carbon-11 radionuclide. This study examines the merits and advantages of a captive solvent 'loop method' of radiolabeling four tracers with the carbon-11 radionuclide, producing the radioligands [C]ER-176, [C]MRB, [C]mHED, and [C]PiB. The 'loop method' is compared against the traditional reactor-based method of carbon-11 methylation in the course of synthesizing the same radiotracers on the identical automated platform. Further, a complete overview of the clinical research preparation of the [C]ER-176 radiotracer is presented. As demonstrated by the production of [C]ER-176, the captive solvent 'loop method' of heterogeneous alkylation proved to be more efficient, with excellent radiochemical purity (99.6 ± 0.6%, n = 25), higher and more consistent radiochemical yield (end of synthesis (EOS) = 5.4 ± 2.2 GBq, n = 25) compared to the reactor method (EOS = 1.6 ± 0.5 GBq, n = 6), increased molar activity (loop method = 194 ± 66 GBq/µmol, n = 25; reactor method = 132 ± 78 GBq/µmol, n = 6), along with an average 5 min shorter reaction sequence.
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