Synthesis, radiosynthesis and In vivo evaluation of 5-[3-(4-Benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-[11C]one, as a potent NR1A/2B subtype selective NMDA PET radiotracer

Recently, a new series of potent and highly subtype-selective 1-(heteroarylalkynyl)-4-benzylpiperidine antagonists of the NMDA receptors has been described by Pfizer Laboratories. In this series, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzoimidazol-2-one (1) was identified as a selective antagonist for the NR1A/2B subtype, displaying IC50 values for inhibition of the NMDA responses of 5.3 nM for this subtype (compared to NR1A/2A: 35 μM and NR1A/2C>100 μM) and was active in rat at a relatively low dosage (10 mg/kg po). Derivative 1 has been synthesized in four chemical steps in good overall yield and labelled with carbon-11 <f><fen><cp type="lpar" STYLE="S">T<NU>1</NU>/2: 20.4 min<cp type="rpar" STYLE="S"></fen></f> at its benzoimidazolone ring using [11C]phosgene. The pharmacological profile of [11C]-1 was evaluated in vivo in rats with biodistribution studies and brain radioactivity monitored with intracerebral radiosensitive β-microprobes. The brain uptake of [11C]-1 was extremely low (0.07% I.D./mL on average at 30 min) and rather uniform across the different brain structures. This in vivo brain regional distribution of [11C]-1 did not match with autoradiographic or binding data obtained with other NR2B subtype-selective NMDA ligands. Competition studies with ifenprodil (20 mg/kg, ip, 30 min before the radiotracer injection) failed to demonstrate specific binding of the radiotracer in the brain. In view of these results, and especially considering the low brain penetration of the radiotracer, [11C]-1 does not have the required properties for imaging NMDA receptors using positron emission tomography. [Copyright &y& Elsevier]