Development and validation of [¹⁸F]DPA714 automated radiosynthesis, a PET radiotracer for neuroinflammation imaging

Context
TSPO protein (Tryptophan-rich Sensory Protein transducer of Oxygen) is involved in several important cellular processes, such as apoptosis and cellular proliferation regulation. In healthy brain, TSPO expression is negligible, but under neuroinflammatory conditions, TSPO expression is markedly increased in activated microglial cells, which makes it a suitable biomarker for positron emission tomography imaging of neuroinflammation. Several TSPO radioligands have been developed as non-invasive molecular imaging tools to assess neuroinflammation in numerous disorders such as neurodegenerative and cardiovascular diseases, cancers, and infections such as severe COVID. The most considered radioligand is currently a derivative of pyrazolopyrimidine named [¹⁸F]DPA714 and used for different clinical trials to monitor neuroinflammation and/or to help to select the most effective therapy.
[¹⁸F]DPA714 is currently involved in many clinical trials all over the word. However, none trial has been registered yet around Marseille. Thus, our purpose was to develop and validate the automated radiosynthesis of [¹⁸F]DPA714 on our synthesizer module with the different quality controls associated to constitute the investigational medicinal product dossier (IMPD).

Materials & methods
The multi-step radiosynthesis was designed based on the literature¹. The radiosynthesis sequence writing was carried out with the software soft PLC. The sequence optimization was conducted through water and fluorinated tests. Different quality controls were realized according to European Pharmacopeia (Eur. Pharm.)² requirements and through development of analytical methods by High Performance Liquid Chromatography.

Results
The radiosynthesis programming sequence was developed, implemented on the synthesizer module and optimized through water and fluorinated tests. The production of one batch was performed and [¹⁸F]DPA714 was obtained in a radiochemical yield decay corrected of 22% which is similar to yields reported in the literature and with a radiochemical purity superior to 95%.
The developed analytical method with the non-radioactive DPA714 allowed the determination of [¹⁸F]DPA714 identity and purity. Thanks to the other quality control tests conducted as described in the Eur. Pharm., we showed that our [¹⁸F]DPA714 was pharmaceutically and microbiologically safe for intravenous injection.

Conclusion
To our knowledge, we are the first to develop and validate the automated radiosynthesis of [¹⁸F]DPA714 on the Modular-lab Pharm Tracer^®. All the work carried out contributes to the constitution of the IMPD, an essential element for the realization of future clinical trials involving this radiotracer at CERIMED.
1. Kuhnast et al., 2012 ; 2. Eur.Pharm. 10.0, 2.2.46, 86 (01.2020)

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