A one-pot radiosynthesis of [18F]FMPEP-d2 for imaging the cannabinoid receptor 1

Abstract

(3R,5R)-5-(3-([¹⁸F]fluoromethoxy-d₂)phenyl)-3-(((R)-1-phenylethyl)amino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one ([¹⁸F]FMPEP-d₂) is a promising positron emission tomography (PET) radiopharmaceutical for the imaging of cannabinoid type 1 receptors in human studies. To facilitate widespread use of [¹⁸F]FMPEP-d₂ we herein report a simplified one-pot synthesis procedure that is broadly applicable for ¹⁸F-fluoromethylation of phenols and can be applied for routine clinical production using a commercial radiofluorination module (GE TRACERlab FX2 N). The present method overcomes previous challenges in the [¹⁸F]FMPEP-d₂ synthesis related to intermediate purification of a [¹⁸F]fluoromethyl building block by using ditosylmethane-d₂ and reacting it directly with (3R,5R)-5-(3-hydroxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluoromethylphenyl)pyrrolidine-2-one in a one-pot nucleophilic reaction with [¹⁸F]fluoride (K₂CO₃, K₂₂₂, CH₃CN, 80 °C, 10 min). After purification of the product by semi-preparative HPLC under isocratic conditions and formulation, [¹⁸F]FMPEP-d₂ was obtained in a decay-corrected radiochemical yield of 8 ± 1 %, a radiochemical purity >95 % and a molar activity of 322 ± 101 GBq/µmol in a synthesis time of 70 ± 5 min (n = 8). Validation and regulatory submission of [¹⁸F]FMPEP-d₂ is underway with the new methodology and will facilitate widespread human use as well as multi-center clinical trials.