Improved work-up procedure for the production of [18F]flumazenil and first results of its use with a high-resolution research tomograph in human stroke

Abstract: Introduction: The central benzodiazepine receptor (cBZR)–gamma-aminobutyric acid (GABAA) receptor complex in the human brain plays an important role in many neurological and psychiatric disorders. 18F-Labeled flumazenil ([18F]FZ) provides a potentially useful tracer to investigate those disorders by means of positron emission tomography (PET). Methods: [18F]Flumazenil was synthesized from its nitro-precursor Ro 15-2344 in DMF at high temperatures between 150°C and 160°C. Other solvents like acetonitrile and dimethylsulfoxide were also investigated as reaction media. A new HPLC method for the final purification of [18F]FZ was developed to circumvent some difficulties associated with a previously published procedure sometimes led to a contamination of [18F]FZ with Ro 15-2344. The final purification of the radiotracer was achieved using a Waters Symmetry Prep C18 HPLC column with elution with 0.05 M sodium acetate (NaOAc) buffer (pH 5)/THF/MeOH (80:10:10). Results: [18F]FZ could be synthesized in reproducible radiochemical yields (RCYs) of 15–20% (decay corrected to EOB) after 80 min overall synthesis time. The synthesized [18F]FZ was applied for the first time in a human PET study in a patient with ischemic right middle cerebral artery stroke using the HRRT high-resolution research scanner (Siemens Medical Solution, Knoxville, TN, USA). Conclusions: [18F]FZ is a potentially useful GABA receptor-binding PET ligand. A modified procedure for its preparation in reproducibly high radiochemical yields has been described and the [18F]FZ thus produced has been used successfully in a pilot clinical study. [Copyright &y& Elsevier]