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.