Iodine-123 labelled Z-(R,R)-IQNP:: a potential radioligand for visualization of M1 and M2 muscarinic acetylcholine receptors in Alzheimer's disease

Z-(R)-1-Azabicyclo[2.2.2]oct-3-yl (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate(Z-IQNP) has high affinity to the M-1 and M-2 muscarinic acetylcholine receptor (mAChR) subtypes according to previous in vitro and in vivo studies in rats. In the present study iodine-123 labelled Z-IQNP was prepared for in vivo single-photon emission tomography (SPET) studies in cynomolgus monkeys. SPET studies with Z-[I-123]IQNP demonstrated high accumulation in monkey brain (>5% of injected dose at 70 min p.i.) and marked accumulation in brain regions such as the thalamus, the neocortex, the striatum and the cerebellum. Pretreatment with the nonselective mAChR antagonist scopolamine (0.2 mg/kg) inhibited Z-[I-123]IQNP binding in all these regions. The percentage of unchanged Z-[I-123]IQNP measured in plasma was less than 10% at 10 min after injection, which may be due to rapid hydrolysis, as has been demonstrated previously with the E-isomer of IQNP. Z-[I-123]IQNP showed higher uptake in M-2-rich regions, compared with previously obtained results with E-[I-123]IQNP. In conclusion, the radioactivity distribution from Z-[I-123]IQNP in monkey brain indicates that Z-[I-123]IQNP binds to the M-1- and M-2-rich areas and provides a high signal for specific binding, and is thus a potential ligand for mAChR imaging with SPET.