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

• Published in: Applied radiation and isotopes 2006-03, Vol.64 (3), p.348-354
• Main Authors: Thominiaux, Cyrille, de Bruin, Béatrice, Bramoullé, Yann, Hinnen, Françoise, Demphel, Stéphane, Valette, Heric, Bottlaender, Michel, Besret, Laurent, Kassiou, Michael, Dollé, Frédéric
• Format: Article
• Language: English
• Subjects: Amidines - analysis; Amidines - chemical synthesis; Carbon-11; Drug Evaluation, Preclinical; Isotope Labeling - methods; Methyl triflate; NMDA receptor; Positron emission tomography; Positron-Emission Tomography - methods; Radiopharmaceuticals - analysis; Radiopharmaceuticals - chemical synthesis; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors
• ISSN: 0969-8043; 1872-9800
• DOI: 10.1016/j.apradiso.2005.08.005

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 (K i=0.7 nM versus [ 3H]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 [ 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]CO 2 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.