Radiosynthesis of (E)-N-(2-[11C]methoxybenzyl)-3-phenyl-acrylamidine, a novel subnanomolar NR2B subtype-selective NMDA receptor antagonist

Recently, a novel series of amidines has been described, exhibiting high NR2B-subtype selective N-methyl-D-aspartate (NMDA) antagonist activity with nanomolar or subnanomolar affinity. Within the styrylamidine subclass, (E)-N-(2-methoxybenzyl)-3-phenyl-acrylamidine (1), displayed the highest affinity (Ki=0.7 nM versus [3H]ifenprodil) and was considered an appropriate candidate for isotopic labelling with carbon-11 (T1/2: 20.38 min) at its methoxy group for imaging of NMDA receptors with PET. Derivative 1 has been labelled from the corresponding nor-analogue using [11C]methyl triflate and the following experimental conditions : (1) trapping at −10 °C of [11C]methyl triflate in 300 μL of acetone containing 0.6–0.8 mg of precursor 5 (2.4–3.2 μmol) and 5 μL of a 3 M solution of NaOH in water (about 5 eq.); (2) concentration to dryness of the reaction mixture (at 110 °C, using a helium stream for 1–2 min); (3) taking up the residue with 0.5 mL of the HPLC mobile phase and (4) purification using semi-preparative HPLC (SymmetryPrep® C-18, Waters, 300×7.8 mm). Typically, starting from a 1.5 Ci (55.5 GBq) [11C]CO2 production batch, 120–240 m Ci (4.44–8.88 GBq) of [11C]-1 (20–40% decay-corrected radiochemical yield, n=5) was obtained within a total synthesis time of 25–30 min. Specific radioactivities ranged from 0.8 to 1.2 Ci/μmol (29.6–44.4 GBq/μmol) at the end of radiosynthesis. No attempts were made to further optimise these reactions, as sufficient material was obtained to allow for preliminary pharmacological characterisation.