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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 T1/2: 20.4 min 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]

In recent years, there has been considerable effort to design and synthesize radiotracers suitable for use in Positron Emission Tomography (PET) imaging of the α4β2 neuronal nicotinic acetylcholine receptor (nAChR) subtype. A new fluoropyridinyl derivative of (−)-cytisine (1), namely (−)-9-(2-fluoropyridinyl)cytisine (3, Ki values of 24 and 3462 nM for the α4β2 and α7 nAChRs subtypes, respectively) has been synthesized in four chemical steps from (−)-cytisine and labelled with fluorine-18 (T1/2: 119.8 min) using an efficient two-step radiochemical process [(a) nucleophilic heteroaromatic ortho-radiofluorination using the corresponding N-Boc-protected nitro-derivative, (b) TFA removal of the Boc protective group]. Typically, 20–45 mCi (0.74–1.67 GBq) of (−)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3, 2–3 Ci/μmol or 74–111 GBq/μmol) were easily obtained in 70–75 min starting from a 100 mCi (3.7 GBq) aliquot of a cyclotron-produced [18F]fluoride production batch (20–45% non decay-corrected yield based on the starting [18F]fluoride). The in vivo pharmacological profile of (−)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) was evaluated in rats with biodistribution studies and brain radioactivity monitoring using intracerebral radiosensitive β-microprobes. The observed in vivo distribution of the radiotracer in brain was rather uniform, and did not match with the known regional densities of nAChRs. It was also significantly different from that of the parent compound (−)-[3H]cytisine. Moreover, competition studies with (−)-nicotine (5 mg/kg, 5 min before the radiotracer injection) did not reduce brain uptake of the radiotracer. These experiments clearly indicate that (−)-9-(2-[18F]fluoropyridinyl)cytisine ([18F]-3) does not have the required properties for imaging nAChRs using PET. [Copyright &y& Elsevier]