title: Radiosynthesis of (E)-N-(2-[11C]methoxybenzyl)-3-phenyl-acrylamidine, a novel subnanomolar NR2B subtype-selective NMDA receptor antagonist.
abstract: 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 [(3)H]ifenprodil) and was considered an appropriate candidate for isotopic labelling with carbon-11 (T(1/2): 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 [(11)C]methyl triflate and the following experimental conditions : (1) trapping at -10 degrees C of [(11)C]methyl triflate in 300 microL of acetone containing 0.6-0.8 mg of precursor 5 (2.4-3.2 micromol) and 5 microL of a 3M solution of NaOH in water (about 5 eq.); (2) concentration to dryness of the reaction mixture (at 110 degrees 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 x 7.8 mm). Typically, starting from a 1.5 Ci (55.5 GBq) [(11)C]CO(2) production batch, 120-240 m Ci (4.44-8.88 GBq) of [(11)C]-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/micromol (29.6-44.4 GBq/micromol) 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.
authors.affiliation: Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, CEA/DSV, 4 place du Général Leclerc, F-91401 Orsay, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Thominiaux
authors.forename: Béatrice
authors.initials: B
authors.lastname: de Bruin
authors.forename: Yann
authors.initials: Y
authors.lastname: Bramoullé
authors.forename: Françoise
authors.initials: F
authors.lastname: Hinnen
authors.forename: Stéphane
authors.initials: S
authors.lastname: Demphel
authors.forename: Heric
authors.initials: H
authors.lastname: Valette
authors.forename: Michel
authors.initials: M
authors.lastname: Bottlaender
authors.forename: Laurent
authors.initials: L
authors.lastname: Besret
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dollé
mesh_terms: D000578:Amidines / Q000032:analysis* / Q000138:chemical synthesis*; D004353:Drug Evaluation, Preclinical; D007553:Isotope Labeling / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000032:analysis / Q000138:chemical synthesis; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D000578:Amidines; C509841:N-(2-methoxybenzyl)-3-phenylacrylamidine; C121001:NR2B NMDA receptor; D019275:Radiopharmaceuticals; D016194:Receptors, N-Methyl-D-Aspartate