Lionel Libert

Production at the Curie Level of No-Carrier-Added 6-18F-Fluoro-l-Dopa

6-18F-fluoro-l-dopa (18F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier-added (NCA) nucleophilic method has several advantages. These include much higher available activity and specific activity. Recently, we have described an NCA enantioselective synthesis using a chiral phase-transfer catalyst. However, some chemicals were difficult to implement into a commercially available synthesizer, restricting access to this radiopharmaceutical to only a few PET centers. Methods: In this paper, 2 important chemical improvements are proposed to simplify production of 18F-FDOPA, resulting in straightforward automation of the synthesis in a commercially available module. Results: First, a fast, simple, and reliable synthesis of 2-18F-fluoro-4,5-dimethoxybenzyl iodide on a solid-phase support was developed. Second, a phase-transfer catalyst alkylation of a glycine derivative at room temperature was used to enable enantioselective carbon–carbon bond formation. After hydrolysis and high-performance liquid chromatography purification, a high enantiomeric excess of 18F-FDOPA (∼97%) was obtained using a chiral catalyst available from a biphenyl 3 substrate. The total synthesis time was 63 min, and the decay-corrected radiochemical yield was 36% ± 3% (n = 8). Conclusion: By exploiting the advantages of this NCA approach, using a starting activity of 185 GBq of NCA 18F-fluoride, high activities of 18F-FDOPA (>45 GBq) with high specific activity (≥753 GBq/μmol) are now available at the end of synthesis for use in clinical investigations.

Microwave-Assisted Synthesis of Vinyl Esters through Ruthenium-Catalyzed Addition of Carboxylic Acids to Alkynes

A rapid and efficient method is described for the selective synthesis of enol esters via the microwave-accelerated addition of carboxylic acids to terminal alkynes. The method employs the readily available [RuCl2(p-cymene)(PPh3)] complex as catalyst without the need of bases, and reactions are complete in 20 min.

Automated production at the curie level of no‐carrier‐added 6‐[18F]fluoro‐ l‐dopa and 2‐[18F]fluoro‐ l‐tyrosine on a FASTlab synthesizer

An efficient, fully automated, enantioselective multi-step synthesis of no-carrier-added (nca) 6-[(18)F]fluoro-L-dopa ([(18)F]FDOPA) and 2-[(18)F]fluoro-L-tyrosine ([(18)F]FTYR) on a GE FASTlab synthesizer in conjunction with an additional high- performance liquid chromatography (HPLC) purification has been developed. A PTC (phase-transfer catalyst) strategy was used to synthesize these two important radiopharmaceuticals. According to recent chemistry improvements, automation of the whole process was implemented in a commercially available GE FASTlab module, with slight hardware modification using single use cassettes and stand-alone HPLC. [(18)F]FDOPA and [(18)F]FTYR were produced in 36.3 ± 3.0% (n = 8) and 50.5 ± 2.7% (n = 10) FASTlab radiochemical yield (decay corrected). The automated radiosynthesis on the FASTlab module requires about 52 min. Total synthesis time including HPLC purification and formulation was about 62 min. Enantiomeric excesses for these two aromatic amino acids were always >95%, and the specific activity of was >740 GBq/µmol. This automated synthesis provides high amount of [(18)F]FDOPA and [(18)F]FTYR (>37 GBq end of synthesis (EOS)). The process, fully adaptable for reliable production across multiple PET sites, could be readily implemented into a clinical good manufacturing process (GMP) environment.

In Vivo PET/CT in a Human Glioblastoma Chicken Chorioallantoic Membrane Model: A New Tool for Oncology and Radiotracer Development

For many years the laboratory mouse has been used as the standard model for in vivo oncology research, particularly in the development of novel PET tracers, but the growth of tumors on chicken chorioallantoic membrane (CAM) provides a more rapid, low cost, and ethically sustainable alternative. For the first time, to our knowledge, we demonstrate the feasibility of in vivo PET and CT imaging in a U87 glioblastoma tumor model on chicken CAM, with the aim of applying this model for screening of novel PET tracers. Methods: U87 glioblastoma cells were implanted on the CAM at day 11 after fertilization and imaged at day 18. A small-animal imaging cell was used to maintain incubation and allow anesthesia using isoflurane. Radiotracers were injected directly into the exposed CAM vasculature. Sodium 18F-fluoride was used to validate the imaging protocol, demonstrating that image-degrading motion can be removed with anesthesia. Tumor glucose metabolism was imaged using 18F-FDG, and tumor protein synthesis was imaged using 2-18F-fluoro-l-tyrosine. Anatomic images were obtained by contrast-enhanced CT, facilitating clear delineation of the tumor, delineation of tracer uptake in tumor versus embryo, and accurate volume measurements. Results: PET imaging of tumor glucose metabolism and protein synthesis was successfully demonstrated in the CAM U87 glioblastoma model. Catheterization of CAM blood vessels facilitated dynamic imaging of glucose metabolism with 18F-FDG and demonstrated the ability to study PET tracer uptake over time in individual tumors, and CT imaging improved the accuracy of tumor volume measurements. Conclusion: We describe the novel application of PET/CT in the CAM tumor model, with optimization of typical imaging protocols. PET imaging in this valuable tumor model could prove particularly useful for rapid, high-throughput screening of novel radiotracers.