Abstract View

Introduction: It is well-established that the translocator protein (TSPO), a mitochondrial membrane protein overexpressed in activated microglia, is a hallmark of numerous neurological disorders including neurodegenerative diseases, brain injury, and inflammatory conditions. In this context, TSPO PET imaging has become an essential tool for the in vivo assessment of neuroinflammatory processes. First-generation TSPO radiotracers, such as [¹¹C]PK11195, have been extensively used; however, they present several limitations, including high non-specific binding, low signal-to-noise ratio, and suboptimal brain kinetics ^[1-4]. Second-generation ligands, including [¹⁸F]DPA-714, have demonstrated enhanced affinity for TSPO, improved brain penetration, and superior imaging contrast. This enhances their suitability for clinical PET imaging of neuroinflammatory processes,^[3] which in turn generates a need for multi-dose, industrialized, and GMP-compatible radiosynthesis processes.

Despite multiple reports describing the radiosynthesis of [¹⁸F]DPA‑714 with decay‑corrected radiochemical yields of 25–50% ^[1-3], robust process designs suitable for routine automated and cassette‑based manufacturing—now considered the gold standard for PET tracer production—remained limited. This work addresses this radiosynthetic gap by reporting a fully automated, high-yielding and scalable radiosynthesis of [¹⁸F]DPA-714 using the Trasis AllinOne synthesizer, specifically designed to support reliable high-activity production for multi-dose clinical applications.

Methods: Using a standard cassette configuration compatible with an AIO18 HPLC, the automated process was developed through the optimization of key parameters. These included the selection of the QMA eluent (K₂₂₂/K₂CO₃ followed by a drying step), precursor amount, and radiolabelling conditions (solvent, temperature, and reaction time). In parallel, different HPLC mobile phases and flow rates were evaluated to achieve efficient purification of [¹⁸F]DPA-714 from radiochemical and chemical impurities. Finally, the reformulation step was optimized using SPE cartridges, including trapping, elution with ethanol, and dilution with an appropriate buffer to obtain a final injectable solution.

Results: This optimized process enabled the robust production of [18F]DPA-714 with non-decay-corrected yields of 50 ± 5% for a total synthesis time of approximately 60 minutes, corresponding to 70 ± 5% decay-corrected yields. Importantly, these performances were maintained at high production scales, including three high-activity runs (>150 GBq starting activity), consistently delivering similar yields and demonstrating the suitability of the method for multi-dose production.

The product demonstrated excellent stability with radiochemical puritiy consistently above 99% at End of Synthesis and remaining above 97% after 8 hours at room temperature. All other QC parameters comply with the general monograph of the Ph. Eur.

Conclusion: Our work makes a fully automated and high-scale production of [¹⁸F]DPA-714 available to research, translational and clinical teams seeking to advance TSPO-PET imaging and the use of neuro-inflammatory processes as the basis of a new diagnostic tool.£

REFERENCES

[1] McCauley KS, Wilde JH, Bufalino SM, Neumann KD. An automated radiosynthesis of [18F]DPA-714 on a commercially available radiosynthesizer, Elixys Flex/Chem. Appl Radiat Isot. 2022 Feb;180:110032. doi: 10.1016/j.apradiso.2021.110032. 

[2] Vāvere AL, Ghosh A, Amador Diaz V, Clay AJ, Hall PM, Neumann KD. Automated radiosynthesis of [¹⁸F]DPA-714 on a commercially available IBA Synthera®. Appl Radiat Isot. 2024 May;207:111257. doi: 10.1016/j.apradiso.2024.111257

[3] James ML, Fulton RR, Vercoullie J, Henderson DJ, Garreau L, Chalon S, Dolle F, Costa B, Guilloteau D, Kassiou M. DPA-714, a new translocator protein-specific ligand: synthesis, radiofluorination, and pharmacologic characterization. J Nucl Med. 2008 May;49(5):814-22. doi: 10.2967/jnumed.107.046151.

[4] Damont A, Hinnen F, Kuhnast B, Schollhorn-Peyronneau MA, James M, Luus C, Tavitian B, Kassiou M, Dolle F. Radiosynthesis of [F-18]DPA-714, a selective radioligand for imaging the translocator protein (18 kDa) with PET. J. Label. Compd. Radiopharm. 2008, 51(7-8), 286-292. doi: 10.1002/jlcr.1523.