Automated radiosynthesis of high specific activity [¹¹C]MeOTf and clinical-grade [¹¹C]PiB using a commercial Synthra synthesizer

Objectives: Carbon-11 labeled Pittsburg compound B ([¹¹C]PiB) is one of the most used β-amyloid-specific PET radiotracers¹. Recently, in our institution, cGMP production of [¹¹C]PiB was requested for human use. As the first human use C-11 tracer at our facility, considerable efforts were focused on the development of efficient and reliable methods for the preparation of [¹¹C]CO₂, [¹¹C]MeI and [¹¹C]MeOTf, as well as the radiosynthesis and quality control of [¹¹C]PiB for human use.

Methods: [¹¹C]CO₂ was produced with a TR-24 cyclotron (Advanced Cyclotron System, Vancouver, Canada) by irradiating of target gas: N₂ containing 0.5% O₂. Then on an automatic MeI-Plus synthesis module (Synthra, Hamburger, Germany), [¹¹C]CO₂ was converted to [¹¹C]CH₄, [¹¹C]MeI and [¹¹C]MeOTf sequentially via gas-phase conversion pathway. On the same module, [¹¹C]MeOTf was used for N-methylation of the precursor 6-OH-BTA-0 in 2-butanone in a glass reactor². The labeling completed in one minute at 50 °C. [¹¹C]PiB was purified by HPLC and formulated as a final sterile 10% ethanol/saline solution. The final dose was subject to quality control protocols prior to release for human administration. Quality control included HPLC to determine chemical purity, radiochemical purity, PiB identity and specific molarity, GC to quantify residual solvent levels, bacterial endotoxin test, radionuclidic purity, decay half-life, pH, appearance and post-release sterility test.

Results: By irradiating C-11 target for 35 minutes using a beam current of 35 μA, 1.2-1.4 Ci of [¹¹C]CO₂ were produced. From which, 950-1050 mCi of [¹¹C]MeI, and 600-800 mCi of [¹¹C]MeOTf were produced respectively, in 12 min from the time of the end of bombardment (EOB). [¹¹C]PiB batches (n=60) were synthesized by directly [¹¹C]MeOTf N-[¹¹C]methylation of 6-OH-BTA-0. Good radiochemical yields (40.2 ± 12.3% referred to [¹¹C]CO₂, decay corrected to EOB) and specific molarities (19.4 ± 5.6 Ci/µmol at EOS) were obtained for [¹¹C]PiB; the total synthesis time was 43-45 min from EOB. Specific molarity was high after optimization; however, with high specific molarity (> 8 Ci/µmol at EOS), under the reverse phase HPLC purification conditions, 0.1% ascorbic acid was needed in the mobile phase to suppress the radiolysis of [¹¹C]PiB occurred on the HPLC column. Only when the QC results met the pre-set criteria, the final dose was released.

Conclusions: A reliable fully automated process reported here allowed us to produce high specific molarity [¹¹C]MeOTf, and synthesize [¹¹C]PiB with good radiochemical yields (~40% decay corrected to EOB) and high specific molarities (15-25 Ci/µmol at EOS). To our knowledge, this is the first report on PiB production for human use with the Synthra module, and the specific molarities achieved are among the highest ones reported using the [¹¹C]CO₂ method³. 60-80 mCi of [¹¹C]PiB was produced in 43 minutes, providing [¹¹C]PiB with high chemical and radiochemical purity. The radiolysis during HPLC purification was suppressed by adding ascorbic acid to the mobile phase. Human studies are being performed with [¹¹C]PiB under an approved IND at our institution. Acknowledgments: We want to thank Dr. Suzanne E. Lapi for constructive discussions and the UAB Cyclotron facility (Jason Rider, Jean P. Appiah and Brian Brooks) for expert provision of carbon-11 and performing routine QC. References: [1] Mathis, C.A., et al., J. Med. Chem. 2003.46,2740-2754. [2] Coliva, C.A., et al., Appl. Radiat .Isot., 2015, 105, 66-71. [3] Editor, Hsieh, C.H., 2012, Positron Emission Tomography Current Clinical and Research Aspects, London, IntechOpen.

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