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

Abstract

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.

Fig. 1

Preliminary PET data from a 64 year-old subject with evidence of mild memory impairment: (A) [¹¹C]PiB, (B) [¹⁸F]FDG, (C) [¹⁸F]FPEB and (D) MRI showing hyperactivity in the hippocampus.

Fig. 2

Schematics of microfluidic flow platform and parameters for the radiosynthesis of [¹⁸F]FPEB: (A) [¹⁸F]fluoride drying concentrator, (B) high resolution syringe pump, (C) storage loop (polyether ether ketone), (D) microfluidic flow reactor, (E) dilution vial, (F) solid phase exchange cartridge. Specifications of the microfluidic flow reactor : volume 8–64 µL, reaction path from 1–8 meter, I.D. 100 µm, temperature range from 25 °C to 220 °C, pressure up to 3.45MPa (500 psi).

Fig. 3

Temperature (A) and flow rate (B) effect of [¹⁸F]FPEB synthesis. (a) Conditions: [¹⁸F]fluoride was trapped on an anion exchange resin (MP1, ORTG, Inc., USA), eluted with nBu₄NHCO₃ (0.075M aqueous solution) and azeotropically dried using standard NanoTek drying macro sequence (see ESI). The temperature effect was screened at a total flow rate of 60 µL/ min and the flow rate was evaluated at 210°C. (b) Radiochemical conversion of [¹⁸F]FPEB (n = 1 per data point) was determined with radio-HPLC (t_R (FPEB) = 7.0 min, t_R (impurity) = 6.2 min, mobile phase: 60/40 CH₃CN/H₂O + 0.1N ammonium formate; Luna 5µ C18 100 Å, λ = 254 nm, 250 × 4.6 mm; flow rate: 1 mL/min).