Microfluidic continuous-flow radiosynthesis of [18F]FPEB suitable for human PET imaging.

The synthesis of fluorine-18 labeled 3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ([18F]FPEB) for imaging metabotropic glutamate receptor subtype type 5 (mGluR5) was achieved with a commercial continuous-flow microfluidics device. This work represents the first positron emission tomography (PET) radiopharmaceutical that is suitable for human use with this technology. We also describe a validated synthesis of [18F]FPEB with a commercial reactor-based system.

First human use of a radiopharmaceutical prepared by continuous-flow microfluidic radiofluorination: proof of concept with the tau imaging agent [18F]T807.

Despite extensive preclinical imaging with radiotracers developed by continuous-flow microfluidics, a positron emission tomographic (PET) radiopharmaceutical has not been reported for human imaging studies by this technology. The goal of this study was to validate the synthesis of the tau radiopharmaceutical 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([18F]T807) and perform first-in-human PET scanning enabled by microfluidic flow chemistry. [18F]T807 was synthesized by our modified one-step method and adapted to suit a commercial microfluidic flow chemistry module. For this proof of concept, the flow system was integrated to a GE Tracerlab FXFN unit for high-performance liquid chromatography purification and formulation. Three consecutive productions of [18F]T807 were conducted to validate this radiopharmaceutical. Uncorrected radiochemical yields of 17 ± 1% of crude [18F]T807 (≈ 500 mCi, radiochemical purity 95%) were obtained from the microfluidic device. The crude material was then purified, and > 100 mCi of the final product was obtained in an overall uncorrected radiochemical yield of 5 ± 1% (n  =  3), relative to starting [18F]fluoride (end of bombardment), with high radiochemical purity (≥ 99%) and high specific activities (6 Ci/µmol) in 100 minutes. A clinical research study was carried out with [18F]T807, representing the first reported human imaging study with a radiopharmaceutical prepared by this technology.

A concise radiosynthesis of the tau radiopharmaceutical, [(18) F]T807.

Fluorine-18 labeled 7-(6-fluoropyridin-3-yl)-5H-pyrido[4,3-b]indole ([(18) F]T807) is a potent and selective agent for imaging paired helical filaments of tau and is among the most promising PET radiopharmaceuticals for this target in early clinical trials. The present study reports a simplified one-step method for the synthesis of [(18) F]T807 that is broadly applicable for routine clinical production using a GE TRACERlab™ FXFN radiosynthesis module. Key facets of our optimized radiosynthesis include development and use of a more soluble protected precursor, tert-butyl 7-(6-nitropyridin-3-yl)-5H-pyrido[4,3-b]indole-5-carboxylate, as well as new HPLC separation conditions that enable a facile one-step synthesis. During the nucleophilic fluorinating reaction with potassium cryptand [(18) F]fluoride (K[(18) F]/K222 ) in DMSO at 130 °C over 10 min the precursor is concurrently deprotected. Formulated [(18) F]T807 was prepared in an uncorrected radiochemical yield of 14 ± 3%, with a specific activity of 216 ± 60 GBq/µmol (5837 ± 1621 mCi/µmol) at the end of synthesis (60 min; n = 3) and validated for human use. This methodology offers the advantage of faster synthesis in fewer steps, with simpler automation that we anticipate will facilitate widespread clinical use of [(18) F]T807.